Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders

ABSTRACT

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I 
                         
as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

CROSS REFERENCE

This application is a continuation of U.S. patent application Ser. No.14/543,020 filed Nov. 17, 2014, which is a divisional patent applicationof U.S. patent application Ser. No. 14/031,163, filed on Sep. 19, 2013,which claims benefit of U.S. provisional patent application No.61/703,969, filed on Sep. 21, 2012, the disclosures of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the treatment of Alzheimer's diseaseand other neurodegenerative and/or neurological disorders in mammals,including humans. This invention also relates to the modulation, inmammals, including humans, of the production of A-□beta peptides thatcan contribute to the formation of neurological deposits of amyloidprotein. More particularly, this invention relates to novel bicyclicpyridinone compounds useful for the treatment of neurodegenerativeand/or neurological disorders, such as Alzheimer's disease and Down'sSyndrome.

BACKGROUND OF THE INVENTION

Dementia results from a wide variety of distinctive pathologicalprocesses. The most common pathological processes causing dementia areAlzheimer's disease (AD), cerebral amyloid angiopathy (CM) andprion-mediated diseases (see, e.g., Haan et al., Clin. Neurol.Neurosurg. 1990, 92(4):305-310; Glenner et al., J. Neurol. Sci. 1989,94:1-28). AD affects nearly half of all people past the age of 85, themost rapidly growing portion of the United States population. As such,the number of AD patients in the United States is expected to increasefrom about 4 million to about 14 million by 2050.

The present invention relates to a group of γ-secretase modulators,useful for the treatment of neurodegenerative and/or neurologicaldisorders such as Alzheimer's disease and Down's Syndrome. (see Ann.Rep. Med. Chem. 2007, Olsen et al., 42: 27-47).

SUMMARY OF THE INVENTION

The present invention is directed to γ-secretase modulators of Formula Ior pharmaceutically acceptable salts thereof as represented below:

wherein:

X is a 5- to 14-membered heteroaryl containing 1-3 heteroatoms;

R¹ is hydrogen, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, or C₂-C₆alkenyl;wherein said alkyl, cycloalkyl or alkenyl is optionally substituted withone to three substituents each independently selected from the groupconsisting of fluoro, hydroxyl and C₁-C₆alkoxy;

A is a C₃-C₆cycloalkyl or a 4- to 10-membered heterocycloalkyl; whereinsaid cycloalkyl or heterocycloalkyl is optionally substituted with oneto three substituents each independently selected from the groupconsisting of halogen and C₁-C₆alkyl;

R^(2a) and R^(2b) for each occurrence is independently hydrogen, fluoro,cyano, —CF₃, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl,C₄-C₈bicycloalkyl, C₂-C₆alkynyl or phenyl; wherein said alkyl, alkenyl,cycloalkyl, bicycloalkyl, alkynyl or phenyl is optionally substitutedwith one to three substituents each independently selected from thegroup consisting of cyano, C₁-C₃alkyl and fluoro; or R^(2a) and R^(2b)together with the carbon to which they are bonded form a 3- to5-membered cycloalkyl optionally substituted with one to three of R⁸;

R³ is hydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl,—(C(R¹⁰)₂)_(t)—(C₃-C₆cycloalkyl), —(C(R¹⁰)₂)_(t)-(4- to 10-memberedheterocycloalkyl), —(C(R¹⁰)₂)_(t)—(C₆-C₁₀aryl), —(C(R¹⁰)₂)_(t)-(5- to10-membered heteroaryl) or —(C(R¹⁰)₂)_(t)—OR¹²; wherein said alkyl,alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionallysubstituted with one to five of R¹¹;

R^(4a) and R^(4b) are each independently hydrogen, —CF₃, or C₁-C₆alkyl,wherein said alkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of—CF₃, cyano and fluoro; or R^(4a) and R^(4b) together with the carbon towhich they are bonded form a 3- to 5-membered cycloalkyl, wherein saidcycloalkyl is optionally substituted with one to three substituents eachindependently selected from the group consisting of —CF₃, cyano, fluoroand C₁-C₆alkyl;

R^(5a) and R^(5b) for each occurrence are each independently hydrogen,—CF₃, or C₁-C₆alkyl, wherein said alkyl is optionally substituted withone to three substituents each independently selected from the groupconsisting of —CF₃, cyano and fluoro; or R^(5a) and R^(5b) together withthe carbon to which they are bonded form a 3- to 5-membered cycloalkyl,wherein said cycloalkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of—CF₃, cyano, fluoro and C₁-C₆alkyl;

R⁶, R⁷ and R⁸ are each independently hydrogen, —CF₃, cyano, halogen,C₁-C₆alkyl, or —OR⁹; provided that R⁶ and R⁷ cannot both be —OH;

R⁹ is hydrogen, C₁-C₆alkyl or —CF₃; wherein said alkyl is optionallysubstituted with one to three substituents each independently selectedfrom the group consisting of cyano and fluoro;

each R¹⁰ is independently hydrogen, halogen, cyano, —CF₃, C₁-C₆alkyl, or—SF₅; wherein said alkyl is optionally substituted with one to threefluoro;

each R¹¹ is independently hydrogen, halogen, —CF₃, —SF₅, —Si(CH₃)₃,—OR¹², C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,—(C(R¹⁰)₂)_(t)—(C₃-C₆cycloalkyl), —(C(R¹⁰)₂)_(t)—(C₆-C₁₀aryl) or—(C(R¹⁰)₂)_(t)-(5- to 10-membered heteroaryl) wherein said —Si(CH₃)₃,alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl is optionallysubstituted with one to five substituents each independently selectedfrom the group consisting of halogen and —CF₃;

each R¹² is hydrogen, C₁-C₆alkyl, —(C(R¹³)₂)_(n)—(C₃-C₆cycloalkyl),—(C(R¹³)₂)_(n)-(4- to 10-membered heterocycloalkyl),—(C(R¹³)₂)_(n)—(C₆-C₁₀aryl), or —(C(R¹³)₂)_(n)-(5- to 10-memberedheteroaryl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl is optionally substituted with one to five of R¹⁴;

each R¹³ is independently hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, halogen, cyano, —CF₃, or —OCF₃;

R¹⁴ is independently hydrogen, —CF₃, cyano, halogen or C₁₋₆alkyl;wherein said alkyl is optionally substituted with one to threesubstituents each independently selected from the group consisting ofhydroxyl, —CF₃, cyano and fluoro; and

each t or n is an integer independently selected from 0, 1, 2 or 3;

each z is an integer independently selected from 1 or 2;

each y is an integer independently selected from 0, 1, 2, 3 or 4.

Compounds of the invention include Examples 1-73 or a pharmaceuticallyacceptable salt thereof as described herein.

Also provided herein are compositions comprising a pharmaceuticallyeffective amount of one or more of the compounds described herein and apharmaceutically acceptable vehicle, carrier or excipient.

The compounds of Formula I are γ-secretase modulators. γ-Secretase playsa role in the production of amyloid beta protein (Aβ) plaques associatedwith Alzheimer's Disease. Accordingly, the compounds of Formula I areuseful in treating a variety of neurodegenerative and/or neurologicaldisorders related to AR production.

Other features and advantages of this invention will be apparent fromthis specification and the appending claims which describe theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are only being utilized to expediteits review by the reader. They should not be construed as limiting theinvention or claims in any manner.

Definitions and Exemplifications

As used throughout this application, including the claims, the followingterms have the meanings defined below, unless specifically indicatedotherwise. The plural and singular should be treated as interchangeable,other than the indication of number:

The term “C₁-C₆alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen) containing from 1 to 6 carbon atoms. Examplesof such substituents include methyl, ethyl, propyl (including n-propyland isopropyl), butyl (including n-butyl, isobutyl, sec-butyl andtert-butyl), pentyl, and hexyl.

The term “C₁-C₃alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen) containing from 1 to 3 carbon atoms. Examplesof such substituents include methyl, ethyl, and propyl (includingn-propyl and isopropyl).

The term “C₂-C₆alkenyl” refers to an aliphatic hydrocarbon containingfrom 1 to 6 carbon atoms and having at least one carbon-carbon doublebond, including straight chain or branched chain groups having at leastone carbon-carbon double bond. Representative examples include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. When the compounds of theinvention contain a C₂-C₆alkenyl group, the compound may exist as thepure E (entgegen) form, the pure Z (zusammen) form, or any mixturethereof.

The term “C₂-C₆alkynyl” refers to an aliphatic hydrocarbon containingfrom 2 to 6 carbon atoms and having at least one carbon-carbon triplebond, including straight chain or branched chain groups having at leastone carbon-carbon triple bond. Representative examples of an alkynylinclude, but are not limited to, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “C₃-C₆cycloalkyl” refers to a carbocyclic substituent obtainedby removing a hydrogen from a saturated carbocyclic molecule and having3 to 6 carbon atoms. A cycloalkyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl may contain one ormore double or triple bonds depending upon the number of carbon atomscontained in the ring (e.g., cyclohexene has one carbon to carbon doublebond or cycloheyne has one carbon to carbon triple bond). Alternatively,a cycloalkyl may be a double ring such as a bicycloalkyl, e.g.,C₄-C₈bicycloalkyl. The term “C₄-C₈bicycloalkyl” refers to a double ringcontaining 4 to 8 carbon atoms. The bicycloalkyl may be fused together,such as bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane,bicyclo[2.2.0]hexane, bicyclo[3.1.0]hexane bicylco[3.2.0]heptanes andoctohydropentalene. The term “bicycloalkyl” also includes bridgedbicycloalkyl systems such as, but not limited to, bicyclo[2.2.1]heptaneand bicyclo[1.1.1]pentane.

The term “C₆-C₁₀aryl” refers to an aromatic substituent containing from6 to 10 carbon atoms, including one ring or two fused rings. Examples ofsuch aryl substituents include, but not limited to, phenyl, naphthyl,and dihydroindenyl.

The term “hydrogen” refers to a hydrogen substituent, and may bedepicted as —H.

The term “hydroxy” or “hydroxyl” refers to —OH. When used in combinationwith another term(s), the prefix “hydroxy” indicates that thesubstituent to which the prefix is attached is substituted with one ormore hydroxy substituents. Compounds bearing a carbon to which one ormore hydroxy substituents are attached include, for example, alcohols,enols and phenol.

The term “cyano” (also referred to as “nitrile”) means —CN, which alsomay be depicted:

The term “halogen” refers to fluorine (which may be depicted as —F),chlorine (which may be depicted as —Cl), bromine (which may be depictedas —Br), or iodine (which may be depicted as —I). In one embodiment, thehalogen is chlorine. In another embodiment, the halogen is fluorine. Inanother embodiment, the halogen is bromine.

The term “(C₁-C₆)alkoxy” as used herein, means a (C₁-C₆)alkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Examples include, but are not limited to, methoxy, ethoxy,and n-propoxy.

The term “4- to 10-membered heterocycloalkyl” refers to a substituentobtained by removing a hydrogen from a saturated or partially saturatedring structure containing a total of 4 to 10 ring atoms, wherein atleast one of the ring atoms is a heteroatom selected from oxygen,nitrogen, or sulfur. Examples of 4- to 10-membered heterocycloalkylsinclude, but are not limited to, dihydrofuranyl, tetrahydrofuranyl,tetrahydropyranyl, dihydrothiophenyl, and tetrahydrothiophenyl. Aheterocycloalkyl alternatively may comprise 2 or 3 rings fused together,wherein at least one such ring contains a heteroatom as a ring atom(i.e., nitrogen, oxygen, or sulfur). In a group that has aheterocycloalkyl substituent, the ring atom of the heterocycloalkylsubstituent that is bound to the group may be the at least oneheteroatom when the heteroatom is nitrogen, or it may be a ring carbonatom, where the ring carbon atom may be in the same ring as the at leastone heteroatom or where the ring carbon atom may be in a different ringfrom the at least one heteroatom. Similarly, if the heterocycloalkylsubstituent is in turn substituted with a group or substituent, thegroup or substituent may be bound to the at least one heteroatom whenthe heteroatom is nitrogen, or it may be bound to a ring carbon atom,where the ring carbon atom may be in the same ring as the at least oneheteroatom or where the ring carbon atom may be in a different ring fromthe at least one heteroatom.

The term “5- to 14-membered heteroaryl” refers to an aromatic ringstructure containing from 5 to 14 ring atoms in which at least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may bea single ring or 2 or 3 fused rings. Examples of heteroaryl substituentsinclude but are not limited to: 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ringsubstituents such as triazolyl, imidazolyl, furanyl, thiophenyl (alsoknown as “thiofuranyl”), pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl;6/5-membered fused ring substituents such as benzothiofuranyl,isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, andanthranilyl; and 6/6-membered fused ring substituents such asquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and1,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ringatom of the heteroaryl substituent that is bound to the group may be theat least one heteroatom when the heteroatom is nitrogen, or it may be aring carbon atom, where the ring carbon atom may be in the same ring asthe at least one heteroatom or where the ring carbon atom may be in adifferent ring from the at least one heteroatom. Similarly, if theheteroaryl substituent is in turn substituted with a group orsubstituent, the group or substituent may be bound to the at least oneheteroatom when the heteroatom is nitrogen, or it may be bound to a ringcarbon atom, where the ring carbon atom may be in the same ring as theat least one heteroatom or where the ring carbon atom may be in adifferent ring from the at least one heteroatom. The term “heteroaryl”also includes pyridyl N-oxides and groups containing a pyridine N-oxidering.

If a substituent is described as being “substituted,” a non-hydrogensubstituent is in the place of a hydrogen substituent on a carbon ornitrogen of the substituent. Thus, for example, a substituted alkylsubstituent is an alkyl substituent wherein at least one non-hydrogensubstituent is in the place of a hydrogen substituent on the alkylsubstituent. To illustrate, monofluoroalkyl is alkyl substituted with afluoro substituent, and difluoroalkyl is alkyl substituted with twofluoro substituents. It should be recognized that if there is more thanone substitution on a substituent, each non-hydrogen substituent may beidentical or different (unless otherwise stated).

If a substituent is described as being “optionally substituted,” thesubstituent may be either (1) not substituted, or (2) substituted. If acarbon of a substituent is described as being optionally substitutedwith one or more of a list of substituents, one or more of the hydrogenson the carbon (to the extent there are any) may separately and/ortogether be replaced with an independently selected optionalsubstituent. If a nitrogen of a substituent is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogens on the nitrogen (to the extent there are any)may each be replaced with an independently selected optionalsubstituent.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably.

If a substituent is described as being optionally substituted with up toa particular number of non-hydrogen substituents, that substituent maybe either (1) not substituted; or (2) substituted by up to thatparticular number of non-hydrogen substituents or by up to the maximumnumber of substitutable positions on the substituent, whichever is less.Thus, for example, if a substituent is described as a heteroaryloptionally substituted with up to 3 non-hydrogen substituents, then anyheteroaryl with less than 3 substitutable positions would be optionallysubstituted by up to only as many non-hydrogen substituents as theheteroaryl has substitutable positions. To illustrate, tetrazolyl (whichhas only one substitutable position) would be optionally substitutedwith up to one non-hydrogen substituent. To illustrate further, if anamino nitrogen is described as being optionally substituted with up to 2non-hydrogen substituents, then the nitrogen will be optionallysubstituted with up to 2 non-hydrogen substituents if the amino nitrogenis a primary nitrogen, whereas the amino nitrogen will be optionallysubstituted with up to only 1 non-hydrogen substituent if the aminonitrogen is a secondary nitrogen.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other(s). Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

It is understood that descriptions of any one substituent, such as R¹,may be combined with descriptions of any other substituents, such as R²,such that each and every combination of the first substituent and thesecond substituent is provided herein the same as if each combinationwere specifically and individually listed. For example, in onevariation, R¹ is taken together with R² to provide an embodiment whereinR¹ is methyl and R² is halogen.

As used herein the terms “Formula I”, “Formula Ia”, “Formula Ib”, and“Formula Ic” may be hereinafter referred to as “compound(s) of theinvention.” Such terms are also defined to include all forms of thecompound of Formulas I, Ia, Ib, and Ic, including hydrates, solvates,isomers, crystalline and non-crystalline forms, isomorphs, polymorphs,and metabolites thereof. For example, the compounds of Formulas I, Ia,Ib and Ic or pharmaceutically acceptable salts thereof, may exist inunsolvated and solvated forms. When the solvent or water is tightlybound, the complex will have a well-defined stoichiometry independent ofhumidity. When, however, the solvent or water is weakly bound, as inchannel solvates and hygroscopic compounds, the water/solvent contentwill be dependent on humidity and drying conditions. In such cases,non-stoichiometry will be the norm.

The compounds of the invention may exist as clathrates or othercomplexes. Included within the scope of the invention are complexes suchas clathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of FormulasI, Ia, Ib, and Ic containing two or more organic and/or inorganiccomponents which may be in stoichiometric or non-stoichiometric amounts.The resulting complexes may be ionized, partially ionized, ornon-ionized. For a review of such complexes, see J. Pharm. Sci., 64 (8),1269-1288 by Haleblian (August 1975).

The compounds of the invention may have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line (—) a solid wedge (

) or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g. specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that the stereoisomer shown ispresent. When present in racemic compounds, solid and dotted wedges areused to define relative stereochemistry, rather than absolutestereochemistry. Racemic compounds possessing such indicated relativestereochemistry are marked with (+/−). For example, unless statedotherwise, it is intended that the compounds of the invention can existas stereoisomers, which include cis and trans isomers, optical isomerssuch as R and S enantiomers, diastereomers, geometric isomers,rotational isomers, and conformational isomers. The compounds of theinvention may exhibit more than one type of isomerism; and mixturesthereof (such as racemates and diastereomeric pairs). Also included areacid addition or base addition salts wherein the counterion is opticallyactive, for example, D-lactate or L-lysine, or racemic, for example,DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formulas I, Ia, Ib and Ic, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that may be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but notlimited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.Certain isotopically-labeled compounds of compounds of the invention forexample those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically-labeled compounds of the invention may generally beprepared by carrying out the procedures disclosed in the Schemes and/orin the Examples and Preparations below, by substituting anisotopically-labeled reagent for a non-isotopically-labeled reagent.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of formula I with anacid whose anion, or a base whose cation, is generally consideredsuitable for human consumption. Pharmaceutically acceptable salts areparticularly useful as products of the methods of the present inventionbecause of their greater aqueous solubility relative to the parentcompound.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids such as acetic,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isothionic, lactic, lactobionic, maleic, malic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids. Suitable organic acids generallyinclude but are not limited to aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic, and sulfonic classes of organicacids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, butyrate, camphorate,camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalenesulfonate, oxalate, palmoate, pectinate,3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, i.e., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl(C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (i.e., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (i.e.,benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulphate and hemicalcium salts.

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention are administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds required to treat the progress of the medical conditionare readily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts. Theterm “therapeutically effective amount” as used herein refers to thatamount of the compound being administered which will relieve to someextent one or more of the symptoms of the disorder being treated.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

Compounds

To further elucidate the compounds of the present invention, thefollowing subgenuses are described below.

Formula Ia depicted below is a subset of Formula I as depicted, whereinz is 1, and R^(5a), R^(5b), R⁶ and R⁷ are each hydrogen. In Formula Ia Xis a 5-membered heteroaryl selected from imidazolyl, pyrazolyl,isothiazolyl, thiazolyl, isoxazolyl, oxazolyl or pyridyl; R¹ is selectedfrom hydrogen, halogen, or C₁-C₃alkyl; y is 0 or 1; R^(2a) and R^(2b)are each independently hydrogen or C₁-C₃alkyl; R^(4a) and R^(4b) areeach independently hydrogen or C₁-C₃alkyl; A is a C₃-C₆cycloalkylselected from cyclobutyl, cyclopentyl or cyclohexyl, or A is a 5- to6-membered heterocycloalkyl selected from tetrahydrofuranyl,tetrahydropyranyl or dihydroisoxazolyl, wherein the cyclobutyl,cyclopentyl cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl ordihydroisoxazolyl are optionally substituted with one to threesubstituents each independently selected from halogen or C₁-C₃alkyl; andR³ is —(C(R¹⁰)₂)_(t)—(C₆-C₁₀aryl), —(C(R¹⁰)₂)_(t)-(5- to 10-memberedheteroaryl) or —(C(R¹⁰)₂)_(t)—OR¹²; wherein said aryl is optionallysubstituted with one to five substituents each independently selectedfrom fluoro, chloro, —CF₃, —SF₅, —OCF₃, —OCHF₂, —OCH₃, —CF₂CF₃, —CF₂CH₃;each R¹² is independently C₆-C₁₀aryl or a 5- to 10-membered heteroaryl,wherein said aryl or heteroaryl is optionally substituted with one tofive fluoro, chloro, CF₃, methyl, or isopropyl; and t is 0 or 1.

In certain embodiments of the invention, in Formula Ia as depictedabove, x is imidazolyl; R¹ is methyl; y is 0; R^(2a) and R^(2b) are eachindependently hydrogen; R^(4a) and R^(4b) are each independentlyhydrogen; A is cyclobutyl; and R³ is (6,7-difluoronaphthylen-1-yl)oxy.

In certain other embodiment of the invention, in Formula Ia as depictedabove, x is imidazolyl; R¹ is methyl; y is 1; one of R^(2a) or R^(2b) ishydrogen and the other is methyl; R^(4a) and R^(4b) are eachindependently hydrogen; A is tetrahydrofuranyl; and R³ is5-trifluoromethylthiophen-2-yl.

Formula Ib depicted below is a subset of Formula I as depicted wherein xis imidazolyl, R³ is phenyl, z is 1, and R^(5a), R^(5b), R⁶ and R⁷ areeach hydrogen. In Formula Ib, as depicted below, R¹ is selected fromhydrogen, halogen, or C₁-C₃alkyl; y is 0 or 1; R^(2a) and R^(2b) areindependently hydrogen or C₁-C₃alkyl; R^(4a) and R^(4b) are eachindependently hydrogen or C₁-C₃alkyl; A is a C₃-C₆cycloalkyl selectedfrom cyclopentyl or cyclohexyl, or A is a 5- to 6-memberedheterocycloalkyl selected from tetrahydrofuranyl, tetrahydropyranyl ordihydroisoxazolyl, wherein the cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl or dihydroisoxazolyl are optionallysubstituted with one to three substituents each independently selectedfrom halogen or C₁-C₃alkyl; m is 1, 2, or 3; and each R¹¹ isindependently selected from hydrogen, fluoro, chloro, —CF₃, —SF₅, —OCF₃,—OCHF₂, —OCH₃, —CF₂CF₃, —CF₂CH₃, or cyclopropyl.

In certain embodiments of the invention, in Formula Ib as depictedabove, R¹ is methyl; y is 1; R^(2a) and R^(2b) are independentlyhydrogen; R^(4a) and R^(4b) are each independently hydrogen; A istetrahydropyranyl; m is 1; and R¹¹ is CF₃. In certain embodiments theCF₃ substituent is attached to the phenyl ring at the para position.

In certain embodiments of the invention, in Formula Ib as depictedabove, R¹ is methyl; y is 1; R^(2a) and R^(2b) are independentlyhydrogen; R^(4a) and R^(4b) are each independently hydrogen; A iscyclohexyl; m is 1 and R¹¹ is chloro. In certain embodiments the chlorosubstituent is attached to the phenyl ring at the para position.

Formula Ic depicted below is a subset of Formula I as depicted wherein xis imidazolyl, R³ is phenyl, A is tetrahydrofuranyl, z is 1, and R^(5a),R^(5b), R⁶ and R⁷ are each independently hydrogen. In Formula Ic, asdepicted below, R¹ is selected from hydrogen, halogen, or C₁-C₃alkyl;R^(2a) and R^(2b) are independently hydrogen or methyl; R^(4a) andR^(4b) are each independently hydrogen or C₁-C₃alkyl; thetetrahydrofuranyl moiety is optionally substituted with one to threesubstituents each independently selected from halogen or C₁-C₃alkyl; andR¹¹ is selected from hydrogen, fluoro, chloro, —CF₃, —SF₅, —OCF₃,—OCHF₂, —OCH₃, —CF₂CF₃, —CF₂CH₃, or cyclopropyl.

In certain other embodiments of the invention, in Formula Ic as depictedabove, R¹ is methyl; R^(2a) and R^(2b) are both hydrogen; one of R^(4a)and R^(4b) is hydrogen and the other is methyl; and R¹¹ is —CF₃. Incertain embodiments the —CF₃ substituent on the phenyl ring is attachedat the para position.

In certain other embodiments of the invention, in Formula Ic as depictedabove, R¹ is methyl; R^(2a) and R^(2b) are both hydrogen; R^(4a) andR^(4b) are both hydrogen; the tetrahydrofuranyl moiety is substitutedwith a single fluoro or methyl substituent; and R¹¹ is —CF₃. In certainembodiments the —CF₃ substituent on the phenyl ring is attached at thepara position.

In certain other embodiments of the invention, in Formula Ic as depictedabove, R¹ is methyl; R^(2a) and R^(2b) are both hydrogen; R^(4a) andR^(4b) are both hydrogen; and R¹¹ is fluoro, chloro, —CF₃, —SF₅, or—OCH₃.

In certain other embodiments of the invention, in Formula Ic as depictedabove, R¹ is methyl; one of R^(2a) and R^(2b) is hydrogen and the otheris methyl; R² is hydrogen; R^(4a) and R^(4b) are both hydrogen; and R¹¹is fluoro, chloro, —CF₃, —OCF₃, —OCHF₂, or —OCH₃.

Formula Id depicted below is a subset of Formula I as depicted wherein xis imidazolyl, A is tetrahydrofuranyl, z is 1, and R^(5a), R^(5b), R⁶and R⁷ are each independently hydrogen. In Formula Id depicted below, R²is hydrogen or methyl; R³ is C₆-C₁₀aryl or a 5- to 6-memberedheteroaryl, wherein said aryl or heteroaryl is optionally substitutedwith one to three R¹¹, wherein each R¹¹ is independently selected fromthe group consisting of fluoro, chloro, —CF₃, —SF₅, —OCH₃, —OCF₃, and—OCHF₂.

In certain embodiments of Formula Id is as depicted above R³ is phenyloptionally substituted with one to three R¹¹ substituents independentlyselected from fluoro, chloro, —CF₃, —SF₅, —OCH₃, —OCF₃, and —OCHF₂.

In certain other embodiments of Formula Id is as depicted above R³ isthiophenyl optionally substituted with one to three R¹¹ substituentsindependently selected from fluoro, chloro, —CF₃, —SF₅, —OCH₃, —OCF₃,and —OCHF₂.

Pharmacology

Alzheimer's Disease (AD) research indicates that the disease isassociated with the build-up of plaques in variable shapes and sizes inthe brain. The primary plaques associated with AD are amyloid betaprotein (Aβ). Aβ is produced when the amyloid protein precursor (APP)undergoes successive proteolysis by β- and γ-secretase (Haas, et al.,“Trafficking and proteolytic processing of APP”, Cold Spring HarborPerspect Med., 2011). γ-Secretase is a large complex of four differentintegral proteins, one of which has been identified as the catalyticcomponent that comprises an unusual membrane-embedded component (DeStrooper, Bart, et al, “Presenilins and γ-Secretase: Structure,Function, and Role in Alzheimer's Disease” Cold Spring Harb Perspect Med2012; 2:a006304). The catalytic components known as presenilins werefirst discovered as sites of missense mutations responsible forearly-onset Alzheimer disease (AD). The encoded multipass membraneproteins were subsequently found to be the catalytic components ofγ-secretases, membrane-embedded aspartyl protease complexes responsiblefor generating the carboxyl terminus of the amyloid b-protein (Aβ) fromthe amyloid protein precursor (APP). (De Strooper, Bart, et al, 2012).Accordingly, targeting γ-secretase proteins as a potential target fordrug discovery in the treatment of Alzheimer's disease has become a mainfocus of Alzheimer's disease research.

The compounds of the present invention are γ-secretase modulators andcan be used for treating conditions or diseases of the central nervoussystem identified to have enhanced gamma secretase activity, such asNiemann-Pick type C; neurological disorders (such as migraine; epilepsy;Alzheimer's disease; Parkinson's disease; brain injury; stroke;cerebrovascular diseases (including cerebral arteriosclerosis, cerebralamyloid angiopathy, hereditary cerebral hemorrhage, and brainhypoxia-ischemia); cognitive disorders (including amnesia, seniledementia, HIV-associated dementia, Alzheimer's disease, Huntington'sdisease, Lewy body dementia, vascular dementia, drug-related dementia,tardive dyskinesia, myoclonus, dystonia, delirium, Pick's disease,Creutzfeldt-Jacob disease, HIV disease, Gilles de la Tourette'ssyndrome, epilepsy, muscular spasms and disorders associated withmuscular spasticity or weakness including tremors, and mild cognitiveimpairment); mental deficiency (including spasticity, Down syndrome andfragile X syndrome); sleep disorders (including hypersomnia, circadianrhythm sleep disorder, insomnia, parasomnia, and sleep deprivation) andpsychiatric disorders such as anxiety (including acute stress disorder,generalized anxiety disorder, social anxiety disorder, panic disorder,post-traumatic stress disorder, agoraphobia, and obsessive-compulsivedisorder); factitious disorders (including acute hallucinatory mania);impulse control disorders (including compulsive gambling andintermittent explosive disorder); mood disorders (including bipolar Idisorder, bipolar II disorder, mania, mixed affective state, majordepression, chronic depression, seasonal depression, psychoticdepression, seasonal depression, premenstrual syndrome (PMS)premenstrual dysphoric disorder (PDD), and postpartum depression);psychomotor disorders; psychotic disorders (including schizophrenia,schizoaffective disorder, schizophreniform, and delusional disorder);drug dependence (including narcotic dependence, alcoholism, amphetaminedependence, cocaine addiction, nicotine dependence, and drug withdrawalsyndrome); eating disorders (including anorexia, bulimia, binge eatingdisorder, hyperphagia, obesity, compulsive eating disorders andpagophagia); sexual dysfunction disorders, urinary incontinence;neuronal damage disorders (including ocular damage, retinopathy ormacular degeneration of the eye, tinnitus, hearing impairment and loss,and brain edema) and pediatric psychiatric disorders (includingattention deficit disorder, attention deficit/hyperactive disorder,conduct disorder, and autism) in a mammal, preferably a human,comprising administering to said mammal a therapeutically effectiveamount of a compound of Formula I, Formula Ia, Formula Ib, and FormulaIc or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compounds of the present invention can beutilized for treating a neurological disorder (such as migraine;epilepsy; Alzheimer's disease; Parkinson's disease; Niemann Pick type C;brain injury; stroke; cerebrovascular disease; cognitive disorder; sleepdisorder) or a psychiatric disorder (such as anxiety; factitiousdisorder; impulse control disorder; mood disorder; psychomotor disorder;psychotic disorder; drug dependence; eating disorder; and pediatricpsychiatric disorder) in a mammal, preferably a human, comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula I or pharmaceutically acceptable salt thereof.

Compounds of the present invention may also be useful for improvingmemory (both short term and long term) and learning ability.

The text revision of the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington D.C.) provides a diagnostic tool foridentifying many of the disorders described herein. The skilled artisanwill recognize that there are alternative nomenclatures, nosologies, andclassification systems for disorders described herein, including thoseas described in the DMS-IV and that terminology and classificationsystems evolve with medical scientific progress.

Formulations

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beadministered topically to the skin or mucosa, that is, dermally ortransdermally. In another embodiment, the compounds of the invention canalso be administered intranasally or by inhalation. In anotherembodiment, the compounds of the invention may be administered rectallyor vaginally. In another embodiment, the compounds of the invention mayalso be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient. A medicament typically contains from about 0.01 mg to about 500mg of the active ingredient, or in another embodiment, from about 1 mgto about 100 mg of active ingredient. Intravenously, doses may rangefrom about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compounds ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of formula I areordinarily combined with one or more adjuvants. Such capsules or tabletsmay contain a controlled-release formulation. In the case of capsules,tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (i.e.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.Injectable preparations (i.e., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting, and/or suspending agents.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibres, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, Finnin and Morgan, J.Pharm. Sci., 88 (10), 955-958 (1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronised suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (i.e., absorbable gel sponges,collagen) and non-biodegradable (i.e., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose,or a heteropolysaccharide polymer, for example, gelan gum, may beincorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone; as amixture, for example, in a dry blend with lactose; or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially. An exemplary therapeutic agent may be, for example, ametabotropic glutamate receptor agonist.

The administration of two or more compounds “in combination” means thatthe two compounds are administered closely enough in time that thepresence of one alters the biological effects of the other. The two ormore compounds may be administered simultaneously, concurrently orsequentially. Additionally, simultaneous administration may be carriedout by mixing the compounds prior to administration or by administeringthe compounds at the same point in time but at different anatomic sitesor using different routes of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention includes the use of a combination of a γ-secretasemodulator compound as provided in Formula I and one or more additionalpharmaceutically active agent(s). If a combination of active agents isadministered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present invention also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of Formula I or a pharmaceutically acceptable salt of thecompound; (b) a second pharmaceutically active agent; and (c) apharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of Formula I, depending on the disease,disorder, or condition to be treated. Pharmaceutically active agentsthat may be used in combination with the compositions of the presentinvention include, without limitation:

(i) acetylcholinesterase inhibitors, such as donepezil hydrochloride(ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigminesulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine(MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also knownas ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361,galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX),tolserine, velnacrine maleate, memoquin, huperzine A (HUP-A;NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;

(ii) amyloid-β (or fragments thereof), such as Aβ₁₋₁₅ conjugated to panHLA DR-binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24,AN-1792, Affitope AD-01, CAD106, and V-950;

(iii) antibodies to amyloid-β (or fragments thereof), such as ponezumab,solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan),ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanizedm266; Lilly), R1450 (Roche), ACU-5A5, huC091, and those disclosed inInternational Patent Publication Nos WO04/032868, WO05/025616,WO06/036291, WO06/069081, WO06/118959, in US Patent Publication NosUS2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, inEuropean Patent Publication Nos EP0994728 and 1257584, and in U.S. Pat.No. 5,750,349;

(iv) amyloid-lowering or -inhibiting agents (including those that reduceamyloid production, accumulation and fibrillization) such as dimebon,davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin,anapsos, oxiracetam, pramiracetam, varenicline, nicergoline,colostrinin, bisnorcymserine (also known as BNC), NIC5-15 (Humanetics),E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2(Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and itsR-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen(FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofenlysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN),indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenacpotassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID),naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (ArcherPharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degradingenzyme (also known as insulysin), the gingko biloba extract EGb-761(ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate(FIBRILLEX, KIACTA), compound W (3,5-bis(4-nitrophenoxy)benzoic acid),NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)),scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR),simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACEinhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683,AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; GammaSecretase Modulators such as ELND-007; and RAGE (receptor for advancedglycation end-products) inhibitors, such as TTP488 (Transtech) andTTP4000 (Transtech), and those disclosed in U.S. Pat. No. 7,285,293,including PTI-777;

(v) alpha-adrenergic receptor agonists, such as guanfacine (INTUNIV,TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa(ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine(also known as neosynephrine), methoxamine, cirazoline, guanfacine(INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, andarmodafinil (NUVIGIL);

(vi) beta-adrenergic receptor blocking agents (beta blockers), such ascarteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE),oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL),sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC),acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate(LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN),butoxamine, and SR 59230A (Sanofi);

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP),butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE),diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine,atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolaminemethylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT,DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL,OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine,imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL),lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON),trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL),oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin(CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin(NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid(DEPAKENE), valproate sodium (DEPACON), 1-benzyl-5-bromouracil,progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022,retigabine, talampanel, and primidone (MYSOLINE);

(ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496;Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE),haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate(DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazinedecanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO),asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN),perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE),ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone(RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA),quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON),blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);

(x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine(ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN),felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT,PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP),nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS),lercanidipine (ZANIDIP), lifarizine, diltiazem (CARDIZEM), verapamil(CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecadin;

(xi) catechol O-methyltransferase (COMT) inhibitors, such as nitecapone,tolcapone (TASMAR), entacapone (COMTAN), and tropolone;

(xii) central nervous system stimulants, such as atomoxetine,reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine,pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN), fenethyllne(CAPTAGON), pipradol (MERETRAN), deanol (also known asdimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidatehydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine(alone or in combination with other CNS stimulants, e.g. ADDERALL(amphetamine aspartate, amphetamine sulfate, dextroamphetaminesaccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate(DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine(VYVANSE), and benzphetamine (DIDREX);

(xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE),prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PREDFORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone(MEDROL); methylprednisolone acetate (DEPO-MEDROL), andmethylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

(xiv) dopamine receptor agonists, such as apomorphine (APOKYN),bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine,dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN),terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL),pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine(NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox andsarizotan;

(xv) dopamine receptor antagonists, such as chlorpromazine,fluphenazine, haloperidol, loxzpine, resperidone, thioridazine,thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE),7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN),domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A,SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN); (xvi)dopamine reuptake inhibitors such as bupropion, safinamide, nomifensinemaleate (MERITAL), vanoxerine (also known as GBR-12909) and itsdecanoate ester DBL-583, and amineptine;

(xvii) gamma-amino-butyric acid (GABA) receptor agonists, such asbaclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL),progabide (GABRENE), and clomethiazole;

(xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant,S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852,JNJ-17216498, HPP-404, SAR-110894,trans-3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanecarboxylic acid ethylamide (PF-3654746 and those disclosed in US PatentPublication Nos US2005-0043354, US2005-0267095, US2005-0256135,US2008-0096955, US2007-1079175, and US2008-0176925; International PatentPublication Nos WO2006/136924, WO2007/063385, WO2007/069053,WO2007/088450, WO2007/099423, WO2007/105053, WO2007/138431, andWO2007/088462; and U.S. Pat. No. 7,115,600);

(xix) immunomodulators such as glatiramer acetate (also known ascopolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic proteinpeptide), dimethyl fumarate, fingolimod (also known as FTY720),roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 andSAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab(RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab(TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX),mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT),mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN),mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN),chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX),alpha-fetoprotein, etanercept (ENBREL), and4-benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2′-bi-1H-pyrrole(also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) andinterferon beta-1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combinationwith a DOPA decarboxylase inhibitor (e.g. carbidopa (SINEMET, CARBILEV,PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluromethyldopa,difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine);

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate(CAMPRAL), besonprodil, ketamine (KETALAR), delucemine, dexanabinol,dexefaroxan, dextromethorphan, dextrorphan, traxoprodil, CP-283097,himantane, idantadol, ipenoxazone, L-701252 (Merck), lancicemine,levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), methadone,(DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine(STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth),ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel(CERESOTAT), gavestinel, and remacimide;

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM),selegiline hydrochloride (I-deprenyl, ELDEPRYL, ZELAPAR),dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine(PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide,isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT),iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (ChiesiFarmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane,desoxypeganine, harmine (also known as telepathine or banasterine),harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN,SUPIRDYL);

(xxv) muscarinic receptor (particularly M1 subtype) agonists, such ascevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE),itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck),L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethoniumbenzensulfonate, furtrethonium p-toluenesulfonate, McN-A-343,oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), andcarbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

(xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol,lamotrigine, perampanel, aniracetam, minaprime, viluzole2,3,4,9-tetrahydro-1H-carbazol-3-one oxime, desmoteplase, anatibant,astaxanthin, neuropeptide NAP (e.g. AL-108 and AL-208; both AllonTherapeutics), neurostrol, perampenel, ispronicline,bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyltartrate(also known as dactylorhin B or DHB), formobactin, xaliproden (XAPRILA),lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE),arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known ascytidine 5′-diphosphocholine), edaravone (RADICUT), AEOL-10113 andAEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known asSA-450 and Msc-1), granulocyte-colony stimulating factor (also known asAX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod(VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220(17-β-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (alsoknown as oligotropin), pyridoxal 5′-phosphate (also known as MC-1),microplasmin, S-18986, piclozotan, NP031112, tacrolimus,L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine,AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes ofHealth), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory BiomedicalResearch), and zonampanel;

(xxvii) nicotinic receptor agonists, such as epibatidine, bupropion,CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328(AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/MemoryPharmaceuticals), R4996 (also known as MEM63908; Roche/MemoryPharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;

(xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such asatomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN),nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN,DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN),maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), andradaxafine;

(xxix) phosphodiesterase (PDE) inhibitors, including (a) PDE1 inhibitors(e.g. vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosedin U.S. Pat. No. 6,235,742, (b) PDE2 inhibitors (e.g.erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and thosedescribed in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g.anagrelide, cilostazol, milrinone, olprinone, parogrelil, andpimobendan), (d) PDE4 inhibitors (e.g. apremilast, ibudilastroflumilast,rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known asRP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast,oglemilast (also known as GRC 3886), tetomilast (also known asOPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline(also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and(e) PDE5 inhibitors (e.g. sildenafil (VIAGRA, REVATIO), tadalafil(CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil, avanafil,dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil,mirodenafil, DA-8159, and those disclosed in International PatentApplications WO2002/020521, WO2005/049616, WO2006/120552, WO2006/126081,WO2006/126082, WO2006/126083, and WO2007/122466), (f) PDE9 inhibitors(e.g. BAY 73-6691 (Bayer AG) and those disclosed in US PatentPublication Nos US2003/0195205, US2004/0220186, US2006/0111372,US2006/0106035, and U.S. Ser. No. 12/118,062 (filed May 9, 2008)), and(g) PDE10 inhibitor such as2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxymethyl]quinoline(PF-2545920), and SCH-1518291;

(xxx) quinolines, such as quinine (including its hydrochloride,dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine,sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), andamodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β-secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754,AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721,E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (alsoknown as LY-2434074), KMI-574, SCH-745966, Ac-rER(N²-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), andCA074Me;

(xxxii) γ-secretase inhibitors and modulators, such as BMS-708163(Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009,L-685458 (Merck), ELAN-G, ELAN-Z,4-chloro-N-[2-ethyl-1(S)-(hydroxymethyl)butyl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT_(1A)) receptorantagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299,S(−)-UH-301, NAN 190, lecozotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT2c) receptor agonists,such as vabicaserin, and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT₄) receptor agonists, suchas PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonists,such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON,NORVAL), methiothepin (also known as metitepine), ritanserin, ALX-1161,ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885,SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046,SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034(Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate,citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX),clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL),fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC),fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL,SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN),venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine,desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine,neuralstem and tesofensine;

(xxxviii) trophic factors, such as nerve growth factor (NGF), basicfibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3),cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin,meteorin, and glial-derived neurotrophic factor (GDNF), and agents thatstimulate production of trophic factors, such as propentofylline,idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

(xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935,JNJ-17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators such as perampanel,mibampator, selurampanel, GSK-729327, andN-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide;and the like.

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of the invention.

The compounds of Formula I, Formula Ia, Formula Ib and Formula Ic, ortheir pharmaceutically acceptable salts, may be prepared by the methodsdescribed below, together with synthetic methods known in the art oforganic chemistry, or modifications and derivatizations that arefamiliar to those of ordinary skill in the art. The starting materialsused herein are commercially available or may be prepared by routinemethods known in the art (such as those methods disclosed in standardreference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS,Vol. I-XII (published by Wiley-Interscience)). Preferred methodsinclude, but are not limited to, those described below.

During any of the following synthetic sequences, it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991; and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999, which are herebyincorporated by reference.

Compounds of Formula I, Formula Ia, Formula Ib, Formula Ic and FormulaId, or their pharmaceutically acceptable salts, can be preparedaccording to the reaction Schemes discussed herein below. Unlessotherwise indicated, the substituents in the Schemes are defined asabove. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the schemes, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the schemes, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. The schemes are representative ofmethods useful in synthesizing the compounds of the present invention.They are not to constrain the scope of the invention in any way.

Scheme 1 illustrates a method for preparing compounds depicted byFormula I. A compound of Formula 1.1 is heated in the presence of anaqueous acid such as hydrochloric acid to furnish the correspondingpyridinone acid of Formula 1.2. The intermediate of Formula 1.2 issubjected to an amide coupling and in situ cyclization reaction with anamino alcohol of Formula 1.3 using a coupling reagent such as HATU[O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate]. The reaction is carried out in the presence of asuitable base such as diisopropylethylamine and in a solvent such asdichloromethane, or N,N′-dimethylformamide.

Scheme 2 illustrates a method for the preparation of compounds ofFormula I. This method commences with reaction of chloroaldehyde 2.1 andan amine of Formula 2.2 using one of many reductive amination protocolsknown to those skilled in the art. For example, this reaction may becarried out by using a reducing agent such as sodiumtriacetoxyborohydride in a suitable solvent such as methanol. Followingpurification, the resultant chloroalkylamine 2.3 may be isolated andstored as its HCl salt. The final compound of Formula I may then beprepared by treating a mixture of chloroalkylamine 2.3, acid 1.2, and abase such as diisopropylethylamine with a suitable amide couplingreagent such as BOP-CI [(bis(2-oxo-3-oxazolidinyl)phosphonic chloride],T3P [propylphosphonic anhydride] or HATU (preferably HATU) in a solventsuch as dichloromethane.

The aminoalcohol coupling partner of Formula 1.3 may be prepared via awide variety of synthetic methods, which can readily be envisioned anddeveloped by one skilled in the art. These include, but are not limitedto, those methods illustrated in Scheme 3. For example, the aminoalcoholof Formula 1.3 may be prepared by carrying out a reductive amination ofa ketone of Formula 3.1 with an amine of Formula 2.2 using one of manyprocedures well known to those skilled in the art. Another methodinvolves reductive amination of an aldehyde of Formula 3.2 with an amineof Formula 2.2 followed by removal of the TBS protecting group by usinga suitable procedure including treatment with methanolic HCl ortetrabutylammonium fluoride. Another method for the synthesis of anaminoalcohol of Formula 1.3 involves alkylation of amine 3.3 with ahalide or mesylate of Formula 3.4. Yet another method involvesalkylation of an amine of Formula 2.2 with bromoalcohol 3.5. Methods ofsynthesis for various amines 2.2, as well as alternative methods ofpreparation of amino alcohols 1.3, are exemplified in the ExperimentalSection. A person skilled in the art, utilizing these disclosures incombination with what is commonly known in the art, may furthergeneralize those syntheses to allow access to a wide variety of amines2.2 and amino alcohols 1.3 including but not limited to variations inR^(2a), R^(2b), y, alternative cycloalkyls and heterocycloalkyls A, andvariously substituted aryls and heteroaryls R³.

Scheme 4 illustrates a method for the preparation of compounds ofFormula 1.1 where R¹—X=4-methylimidazol-1-yl. A 3-aminopyridine compoundof Formula 4.1 is brominated using N-bromosuccinimide in a solvent suchas a mixture of DMSO and water. The resulting intermediate of Formula4.2 is then heated with sodium methoxide in a suitable solvent such as1,4-dioxane to afford a compound of Formula 4.3. The intermediate ofFormula 4.3 is then treated with a mixture of acetic anhydride andformic acid to afford a formamide of Formula 4.4, which is alkylatedwith chloroacetone in the presence of potassium iodide and a base suchas Cs₂CO₃ in a suitable solvent such as DMF. The resulting intermediateof Formula 4.5 is then heated in the presence of NH₄OAc in acetic acidto furnish the imidazole derivative 4.6. Finally, the compound ofFormula 1.1 can be prepared by subjecting the intermediate of Formula4.6 to a carbonylation reaction. This transformation may be carried outby heating a solution of 4.6 and a base such as triethylamine in analcohol solvent such as MeOH under an atmosphere of CO in the presenceof a suitable palladium catalyst such as Pd(dppf)₂Cl₂.DCM[[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex].

Scheme 5 depicts a method for the preparation of compounds of Formula1.1. A pyridyl derivative of Formula 5.1 is oxidized with an oxidizingagent such as mCPBA [3-chloroperoxybenzoic acid] in a suitable solventsuch as dichloroethane to afford the corresponding N-oxide of Formula5.2. The intermediate of Formula 5.2 is then heated in the presence ofTMSCN [trimethylsilyl cyanide] and a base such as triethylamine in asolvent such as acetonitrile to afford the intermediate of Formula 5.3.The corresponding ester may then be prepared from 5.3 in two steps bysubjecting 5.3 to sodium methoxide in a solvent such as THF, followed bytreatment with an alcohol and an acid such as HCl. The ester of Formula5.5 is a versatile intermediate that allows introduction of a variety ofheterocycles R¹X. For example, 5.5 may be subjected to a Suzuki couplingwith a heteroarylboronic acid using methods well known to those skilledin the art [see Tetrahedron 2002, 58, 9633-9695]. Alternatively, thecompound of Formula 5.5 may be coupled to a heterocycle X using a directarylation approach [see D. Lapointe et al., J. Org. Chem. 2011, 76,749-759, and references therein]. For example, 5.5 may be coupled to2-methyl-1,3-oxazole [Formula 5.7 where R¹=Me] by heating in thepresence of a suitable palladium catalyst such as allylpalladiumchloride dimer and a base such as K₂CO₃ in a solvent such as 1,4-dioxaneto afford the intermediate of Formula 1.1 whereR¹X=2-methyl-1,3-oxazol-5-yl.

Alternatively, the compound of Formula 5.5 may be converted to thecorresponding boronate 5.6, using a palladium-catalyzed cross couplingwith a diboron reagent such as5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane in the presence ofpotassium acetate and a palladium catalyst such as Pd(dppf)₂Cl₂.DCM in asolvent such as 1,4-dioxane. The resulting boronate intermediate ofFormula 5.6 can in turn be subjected to a Suzuki coupling with aheteroaryl halide to afford the final compound of Formula 1.1. Anothermethod for the introduction of a heterocycle X involves the use of aChan-Lam coupling [see Tetrahedron Lett. 2003, 44, 3863-3865, andSynthesis 2008, 5, 795-799]. For example, 5.6 may be coupled tosubstituted imidazole 5.8 by heating with a suitable copper source suchas copper oxide or copper acetate in a solvent such as methanol in thepresence of air to afford the intermediate of Formula 1.1 whereX=imidazol-1-yl.

Scheme 6 illustrates a method for the synthesis of compounds of FormulaI. The method commences by heating the compound of Formula 6.1 in anacid such as hydrochloric acid to afford pyridinone acid intermediate6.2. The acid of Formula 6.2 may be subjected to a coupling/cyclizationreaction with an aminoalcohol of Formula 1.3 to afford an intermediateof Formula 6.3 using chemistry described in Scheme 1. The finalcompound, Formula I, may then be formed directly from 6.3 or viaboronate 6.4 using the strategies discussed in Scheme 5. Alternatively,compounds of Formula I where heterocycle X is linked to the pyridinonering via a C—N bond may be formed by nucleophilic aromatic substitution.For example, triazole 6.5 may be coupled to 6.3 by heating in thepresence of a base such as K₂CO₃ and a solvent such as DMSO to affordthe final compound of Formula I where X=triazol-1-yl.

Scheme 7 illustrates a method for the synthesis of compounds of FormulaI where z=1 and R^(4a)═R^(4b)═R^(5a)═R^(5b)═H. The method involvesheating a mixture of a compound of Formula 1.2, dibromoethane, and abase such as Cs₂CO₃ in a solvent such as DMF to afford lactoneintermediate 7.1. The lactone of Formula 7.1 may then be reacted with anamine of Formula 2.2 in the presence of a reagent such as DIBAL(diisobutylaluminum hydride) orbis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct in a solventsuch as THF to afford the amide alcohol of Formula 7.2. Thisintermediate, in turn, may be reacted with methanesulfonyl chloride inthe presence of a base such as triethylamine in a solvent such as THFfollowed by treatment with a base such as1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine to afford thecompound of Formula I wherein z=1 and R^(4a)═R^(4b)═R^(5a)═R^(5b)═H.Alternatively, the ring closure may be carried out in a stepwise fashionby first converting alcohol 7.2 into the corresponding chloride bytreatment with thionyl chloride, followed by deprotonation of the amideNH with a suitable base such as lithium bis(trimethylsilyl)amide toafford the final compound Formula I.

Scheme 8 illustrates a method for the synthesis of amines of Formula8.7, which represent a subset of the general structure of Formula 2.2.The synthesis commences with deprotonation of ethynyl(trimethyl)silaneusing a suitable base such as n-butyllithium in a solvent such as THF.This mixture is then added to a solution of an epoxide of Formula 8.1(see J. Barluenga et al., J. Org. Chem. 1995, 60, 6696-6699) in asolvent such as THF. The resultant alkyne of Formula 8.3 may then besubjected to a Sonogashira coupling with an aryl or heteroaryl halide ofFormula 8.4 (where hal=bromine or iodine) using standard conditionsknown to those skilled in the art (see R. Chinchilla et al., Chem. Soc.Rev. 2011, 40, 5084-5121) to afford a compound of Formula 8.5. Thisintermediate is then subjected to a cyclization reaction mediated by aplatinum catalyst such as di-μ-chlorodichlorobis(ethylene)diplatinum(II)and an acid such as trifluoroacetic acid in a solvent such as CH₂Cl₂ toafford a dihydrofuran intermediate of Formula 8.6. Finally, transferhydrogenation using ammonium formate and a suitable catalyst such aspalladium hydroxide on carbon in a solvent such as methanol affordsamine 8.7, which is subset of Formula 2.2, wherein y=1, R^(2a)═CH₃,R^(2b)═H, A=tetrahydrofuranyl, and R³=aryl or heteroaryl.

Scheme 9 illustrates an alternative method for the synthesis of aminesof Formula 8.7, a subset of the general structure of Formula 2.2. Themethyl ester of Formula 9.1 is reacted with the dianion resulting fromdeprotonation of chloroacetic acid (9.2) with a suitable base such asLDA in a solvent such as THF. The resulting α-chloroketone of Formula9.3 is then treated with a suitable reducing agent such as lithiumtri-tert-butoxyaluminum hydride in a solvent such as diethyl ether toafford chlorohydrin 9.4, which in turn may be converted to thep-nitrobenzoate 9.6 by acylation with p-nitrobenzoyl chloride (9.5) inthe presence of DMAP [4-(dimethylamino)pyridine] and a base such astriethylamine in a solvent such as dichloromethane. The intermediate ofFormula 9.6 is then treated with a base such as potassium hydroxide,resulting in the formation of an epoxide of Formula 9.7. In analogy withScheme 8, epoxide 9.7 may be subjected to ring opening with theacetylide resulting from deprotonation of 8.2 with a base such asn-butyllithium in the presence of dimethylaluminum chloride in a solventsuch as toluene to afford the alkyne of Formula 9.8. This intermediate,in turn, is then subjected to removal of the trimethylsilyl group byexposure to a protic solvent such as methanol and a base such aspotassium carbonate to deliver the deprotected alkyne 9.9. Thisintermediate is then subjected to a Sonogashira coupling with arylhalide 8.4, as described in Scheme 8, to afford the intermediate ofFormula 9.10. This intermediate is then subjected to a cyclizationreaction mediated by a platinum catalyst such asdi-μ-chlorodichlorobis(ethylene)diplatinum(II), an acid such asp-toluenesulfonic acid, and trimethyl orthoformate in a solvent such asMeOH to afford the compound of Formula 9.11. Treatment of 9.11 withboron trifluoride diethyl etherate and a reducing agent such astriethylsilane in a suitable solvent such as dichloromethane deliversthe tetrahydrofuran of Formula 9.12. Finally, removal of the Bocprotecting group by exposure to an acid such as trifluoroacetic acid orhydrochloric acid in a solvent such as dichloromethane or 1,4-dioxaneprovides amine 8.7, which is a subset of Formula 2.2 wherein y=1,R^(2a)═CH₃, R^(2b)═H, A=tetrahydrofuranyl, and R³=aryl or heteroaryl.

When intermediates used to synthesize compounds of the present inventionincorporate a basic center their suitable acid addition salts may beemployed in synthetic pathways. Such suitable addition salts include butare not limited to those derived from inorganic acids, such ashydrochloric, hydrobromic, hydrofluoric, hydroiodic, boric, fluoroboric,phosphoric, nitric, carbonic, and sulfuric acids, and organic acids suchas acetic, benzenesulfonic, benzoic, ethanesulfonic, fumaric, lactic,maleic, methanesulfonic, trifluoromethanesulfonic, succinic,toluenesulfonic, and trifluoroacetic acids. Suitable organic acidsgenerally include but are not limited to aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, lactate,maleate, fumarate, benzoate, p-hydroxybenzoate, phenylacetate,mandelate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, adipate, butyrate, camphorate, cyclopentanepropionate,dodecylsulfate, heptanoate, hexanoate, nicotinate,2-naphthalenesulfonate, oxalate, 3-phenylpropionate, pivalate, andundecanoate.

Furthermore, where intermediates used to prepare compounds of theinvention carry an acidic moiety, suitable salts thereof may be employedfor synthesis. Such salts include alkali metal salts, i.e., lithium,sodium or potassium salts; alkaline earth metal salts, e.g., calcium ormagnesium salts; and salts formed with suitable organic ligands such asamines or quaternary ammonium cations. Organic salts of such acidicintermediates may be made from primary, secondary or tertiary aminessuch as methylamine, diethylamine, ethylenediamine or trimethylamine.Quaternary amines may be prepared by reaction of tertiary amines withagents such as lower alkyl(C₁-C₆) halides (e.g., methyl, ethyl, propyl,and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e.,dimethyl, diethyl, dibutyl, and diamyl sulfates), arylalkyl halides(i.e., benzyl and phenethyl bromides), and others.

Experimental Procedures and Working Example

The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

It will be understood that the intermediate compounds of the inventiondepicted above are not limited to the particular enantiomer shown, butalso include all stereoisomers and mixtures thereof.

Experimental Procedures

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification, includinganhydrous solvents where appropriate (generally Sure-Seal™ products fromthe Aldrich Chemical Company, Milwaukee, Wis.). Products were generallydried under vacuum before being carried on to further reactions orsubmitted for biological testing. Mass spectrometry data is reportedfrom either liquid chromatography-mass spectrometry (LCMS), atmosphericpressure chemical ionization (APCI) or gas chromatography-massspectrometry (GCMS) instrumentation. Chemical shifts for nuclearmagnetic resonance (NMR) data are expressed in parts per million (ppm,δ) referenced to residual peaks from the deuterated solvents employed.

For syntheses referencing procedures in other Examples or Methods,reaction conditions (length of reaction and temperature) may vary. Ingeneral, reactions were followed by thin layer chromatography or massspectrometry, and subjected to work-up when appropriate. Purificationsmay vary between experiments: in general, solvents and the solventratios used for eluents/gradients were chosen to provide appropriateR_(f)s or retention times.

Preparations Preparation P1:5-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrobromide salt (P1)

Step 1. Synthesis of methyl6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2)

To a solution of the known6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (C1, T. Kimuraet al., U.S. Pat. Appl. Publ. 2009, US 20090062529 A1) (44.2 g, 165mmol) in methanol (165 mL) was added triethylamine (46 mL, 330 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (6.7 g, 8.2 mmol). The mixture was degassedseveral times with nitrogen. The reaction was heated to 70° C. under COatmosphere (3 bar) in a Parr apparatus. After 30 minutes, the pressuredropped to 0.5 bar; additional CO was added until the pressure stayedconstant for a period of 30 minutes. The mixture was allowed to cool toroom temperature and filtered through a pad of Celite. The Celite padwas washed twice with methanol and the combined filtrates wereconcentrated under reduced pressure. The residue (88 g) was dissolved inethyl acetate (1 L) and water (700 mL); the organic layer was washedwith water (200 mL), and the aqueous layer was extracted with ethylacetate (500 mL). The combined organic layers were dried over magnesiumsulfate, filtered and concentrated to provide the title compound. Yield:42.6 g, quantitative.

Step 2. Synthesis of5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrobromide salt (P1)

A solution of C2 (3.82 g, 15.9 mmol) in acetic acid (30 mL) and aqueoushydrobromic acid (48%, 30 mL) was heated at reflux for 4 hours. Thereaction was allowed to cool to room temperature, and then chilled in anice bath; the resulting precipitate was collected via filtration andwashed with ice water (30 mL). Recrystallization from ethanol (20 mL)provided the title compound as a light yellow solid. Yield: 3.79 g, 12.6mmol, 79%. LCMS m/z 220.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 12.6 (v brs, 1H), 9.58-9.60 (m, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.88-7.91 (m, 1H),7.09 (d, J=7.4 Hz, 1H), 2.34 (br s, 3H).

Preparation P2:5-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrochloride salt (P2)

A mixture of C2 (12.8 g, 51.8 mmol) and 37% hydrochloric acid (25 mL)was heated at reflux for 18 hours. After the reaction mixture had cooledto room temperature, the solid was collected via filtration; it wasstirred with 1,4-dioxane (2×20 mL) and filtered again, to afford theproduct as a yellow solid. Yield: 13 g, 51 mmol, 98%. ¹H NMR (400 MHz,CD₃OD) δ 9.52 (br s, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.78 (br s, 1H), 7.21(d, J=7.5 Hz, 1H), 2.44 (s, 3H).

Preparation P3:7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione(P3)

Compound P2 (65 g, 250 mmol), 1,2-dibromoethane (52.5 g, 280 mmol) andcesium carbonate (124 g, 381 mmol) were combined inN,N-dimethylformamide (850 mL) and heated at 90° C. for 6 hours. Thereaction mixture was then cooled and filtered through Celite. Afterconcentration of the filtrate in vacuo, the residue was dissolved indichloromethane (500 mL), washed with saturated aqueous sodium chloridesolution (100 mL), washed with water (50 mL), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting solid was washed with acetonitrile to provide the product.Yield: 46.5 g, 190 mmol, 76%. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=1.4Hz, 1H), 7.43 (AB quartet, J_(AB)=7.7 Hz, Δν_(AB)=33.4 Hz, 2H),7.15-7.17 (m, 1H), 4.66-4.70 (m, 2H), 4.38-4.42 (m, 2H), 2.30 (d, J=0.8Hz, 3H).

Preparation P4:2-({cis-2-[2-(Trifluoromethyl)phenoxy]cyclobutyl}amino)ethanol (P4)

Step 1. Synthesis of 2-bromocyclobutanone (C3)

A solution of cyclobutanone (1.28 mL, 17.1 mmol) in chloroform (20 mL)at 0° C. was treated drop-wise with bromine (0.88 mL, 17 mmol) over 25minutes, warmed to room temperature and stirred for 16 hours.Dichloromethane (100 mL) was added and the solution was washed withaqueous sodium thiosulfate solution (50 mL) and saturated aqueous sodiumchloride solution (50 mL). The organic layer was dried over magnesiumsulfate and concentrated in vacuo to afford the title compound as acolorless oil. Yield: 2.45 g, 16.4 mmol, 96%. ¹H NMR (400 MHz, CDCl₃) δ4.97-5.04 (m, 1H), 3.16-3.24 (m, 2H), 2.69-2.80 (m, 1H), 2.18-2.30 (m,1H).

Step 2. Synthesis of 2-[2-(trifluoromethyl)phenoxy]cyclobutanone (C4)

A solution of 2-(trifluoromethyl)phenol (2.72 g, 16.8 mmol) in acetone(147 mL) at 0° C. was treated with cesium carbonate (5.47 g, 16.8 mmol),followed by drop-wise addition of C3 (2.5 g, 16.8 mmol). The mixture wasstirred at 0° C. for 1.5 hours, filtered through Celite, andconcentrated in vacuo to afford the title compound as a colorless oil.Yield: 3.5 g, 15 mmol, 89%. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (br d, J=7.7Hz, 1H), 7.45-7.50 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.07 (br dd, J=7.6,7.6 Hz, 1H), 5.31-5.37 (m, 1H), 2.92-3.00 (m, 2H), 2.55-2.66 (m, 1H),2.19-2.30 (m, 1H).

Step 3. Synthesis of2-({cis-2-[2-(trifluoromethyl)phenoxy]cyclobutyl}amino)ethanol (P4)

A solution of C4 (3.5 g, 15 mmol) and 2-aminoethanol (1.03 g, 16.8 mmol)in 1,2-dichloroethane (100 mL) was treated with sodiumtriacetoxyborohydride (5.62 g, 25.2 mmol) and stirred at roomtemperature for 2 hours. The reaction was treated with acetic acid (4mL) and stirred at room temperature for 16 hours. Aqueous sodiumhydroxide solution (1 N, 100 mL) was added and the mixture was extractedwith dichloromethane (2×100 mL). The combined organic layers were driedover magnesium sulfate and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0% to 70% [10% 2 N ammonia inmethanol/90% ethyl acetate] in ethyl acetate) afforded the titlecompound as a light amber oil. Yield: 2.1 g, 7.6 mmol, 51%. Theindicated cis stereochemistry was tentatively assigned, based on NOE(nuclear Overhauser enhancement) experiments. ¹H NMR (400 MHz, CDCl₃) δ7.57 (br dd, J=7.7, 1.3 Hz, 1H), 7.41-7.47 (m, 1H), 6.99 (br dd, J=7.6,7.6 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.88-4.93 (m, 1H), 3.54-3.66 (m,3H), 2.81-2.88 (m, 1H), 2.63-2.70 (m, 1H), 2.22-2.31 (m, 1H), 1.97-2.16(m, 2H), 1.86-1.94 (m, 1H).

Preparation P5: 2-({[3-(4-Chlorophenyl)cyclohexyl]methyl}amino)ethanol(P5)

Step 1. Synthesis of1-chloro-4-[3-(methoxymethylidene)cyclohexyl]benzene (C5)

To a solution of (methoxymethyl)trimethylsilane (694 mg, 5.75 mmol) intetrahydrofuran (6.8 mL) at −78° C. was added drop-wise sec-butyllithium(1.4 M, 4.45 mL, 6.23 mmol). The solution was warmed to −25° C., held atthat temperature for 30 minutes, then cooled to −78° C. To the reactionwas added drop-wise 3-(4-chlorophenyl)cyclohexanone (prepared accordingto the method of G. A. Whitlock et al., Bioorg. Med. Chem. Lett. 2009,19, 3118-3121) (1.0 g, 4.8 mmol). The reaction was warmed to −25° C. andstirred for 30 minutes, then allowed to slowly warm to room temperatureand stir for 48 hours. The reaction was diluted with tetrahydrofuran (10mL), quenched with saturated aqueous ammonium chloride solution, andextracted three times with ethyl acetate. The combined organic layerswere dried over magnesium sulfate and concentrated in vacuo to providethe crude title compound as a pale yellow oil. Yield: 1.25 g. Thismaterial was used directly in the following step. GCMS m/z 236 (M⁺).

Step 2. Synthesis of 3-(4-chlorophenyl)cyclohexanecarbaldehyde (C6)

Crude C5 (1.25 g from the preceding step, ≦4.8 mmol) was dissolved inaqueous formic acid (3 M, 2.0 mL) and the mixture was refluxed for 2hours. The solution was cooled to room temperature, diluted with waterand extracted twice with ethyl acetate; the combined organic layers weredried over sodium sulfate and concentrated in vacuo. Silica gelchromatography (Gradient: 0% to 100% ethyl acetate in heptanes) affordedthe title compound as an oil, presumed by ¹H NMR to be a roughly 4:1mixture of the two stereoisomers. Yield: 338 mg, 1.52 mmol, 32% over twosteps. GCMS m/z 222 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ [9.65 (d, J=1.4 Hz)and 9.79 (br s), total 1H], 7.25-7.30 (m, 2H), 7.12-7.18 (m, 2H),1.21-2.66 (m, 10H).

Step 3. Synthesis of2-({[3-(4-chlorophenyl)cyclohexyl]methyl}amino)ethanol (P5)

To a solution of C6 (338 mg, 1.52 mmol) in methanol (5 mL) was added2-aminoethanol (139 mg, 2.28 mmol) followed by acetic acid (89 μL, 1.55mmol). The reaction was stirred at reflux for 2 hours, then cooled to 0°C. Sodium borohydride (115 mg, 3.04 mmol) was added and the mixture wasallowed to warm to room temperature. The reaction was diluted with ethylacetate, quenched with water, and then extracted three times with ethylacetate. The combined organic layers were dried over sodium sulfate andconcentrated in vacuo to provide the crude title compound as a liquid.Yield: 362 mg, 1.35 mmol, 89%. This was presumed to be a mixture ofstereoisomers. LCMS m/z 268.3 (M+1). ¹H NMR (400 MHz, CDCl₃),characteristic peaks: δ 7.22-7.28 (m, 2H), 7.10-7.16 (m, 2H), 3.63 (dd,J=5.3, 5.1 Hz, 2H), 2.75 (dd, J=5.3, 5.1 Hz, 2H).

EXAMPLES Example 17-(4-Methyl-1H-imidazol-1-yl)-2-{trans-2-[2-(trifluoromethyl)phenoxy]cyclobutyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,trifluoroacetate salt (1)

Step 1. Synthesis of cis-2-[2-(trifluoromethyl)phenoxy]cyclobutanol (C7)

Compound C4 (3.00 g, 13.0 mmol) was dissolved in methanol (100 mL) andcooled to −78° C. Sodium borohydride (1.48 g, 39.1 mmol) was addedportion-wise over 10 minutes, and the mixture was stirred at −78° C. foran additional 30 minutes before being allowed to warm to roomtemperature and stir for 1 hour. The reaction was quenched withsaturated aqueous sodium bicarbonate solution (100 mL) and extractedwith dichloromethane (2×150 mL). The organic layers were combined,washed with saturated aqueous sodium chloride solution (100 mL), driedover magnesium sulfate, filtered and concentrated under reducedpressure. Two purifications via silica gel chromatography [Gradients: 1)0% to 50% ethyl acetate in heptane; 2) 0% to 50% dichloromethane inheptane] provided the title compound as a colorless oil. The product wastentatively assigned cis stereochemistry on the basis of NOE studies.Yield: 650 mg, 2.80 mmol, 22%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (br dd,J=7.8, 1.2 Hz, 1H), 7.47 (br ddd, J=8.2, 7.8, 1.2 Hz, 1H), 7.04 (br dd,J=7.6, 7.6 Hz, 1H), 6.87 (br d, J=8.4 Hz, 1H), 4.86-4.91 (m, 1H),4.45-4.53 (m, 1H), 2.75 (d, J=9.2 Hz, 1H), 2.27-2.36 (m, 1H), 2.02-2.22(m, 3H).

Step 2. Synthesis of cis-2-[2-(trifluoromethyl)phenoxy]cyclobutylmethanesulfonate (C8)

A mixture of C7 (484 mg, 2.08 mmol), triethylamine (0.87 mL, 6.3 mmol)and dichloromethane (30 mL) was cooled to 0° C. and methanesulfonylchloride (0.32 mL, 4.2 mmol) was added drop-wise over 15 minutes. Afteran additional 30 minutes at 0° C., the reaction was quenched withsaturated aqueous sodium bicarbonate solution (50 mL), and the mixturewas extracted with dichloromethane (2×50 mL). The combined organiclayers were washed with saturated aqueous sodium chloride solution (50mL), dried over magnesium sulfate, filtered and concentrated in vacuo toprovide the title compound as a colorless oil. Yield: 640 mg, 2.06 mmol,99%. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (br dd, J=7.8, 1.2 Hz, 1H),7.45-7.51 (m, 1H), 7.06 (br dd, J=7.7, 7.6 Hz, 1H), 6.88 (br d, J=8.4Hz, 1H), 5.26-5.32 (m, 1H), 5.01-5.06 (m, 1H), 2.95 (s, 3H), 2.53-2.63(m, 1H), 2.37-2.46 (m, 1H), 2.18-2.30 (m, 2H).

Step 3. Synthesis of2-({trans-2-[2-(trifluoromethyl)phenoxy]cyclobutyl}amino)ethanol (C9)

A mixture of C8 (500 mg, 1.61 mmol) and 2-aminoethanol (5 mL) was heatedat 90° C. for 18 hours, then at 100° C. for an additional 24 hours. Thereaction was cooled, diluted with ethyl acetate (100 mL) and washed withaqueous sodium hydroxide solution (1 M, 5×50 mL). The organic layer wasdried over magnesium sulfate, filtered and concentrated in vacuo.Purification via HPLC (Column: Phenomenex Luna C18(2), 5 μm; Mobilephase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid inmethanol; Gradient: 5% to 100% B) afforded the title compound as asolid. Yield; 191 mg, 0.694 mmol, 43%. LCMS m/z 276.3 (M+1). ¹H NMR (400MHz, CDCl₃) δ 8.49 (br s, 1H), 7.56 (br d, J=7.6 Hz, 1H), 7.44-7.50 (m,1H), 7.04 (br dd, J=7.6, 7.6 Hz, 1H), 6.92 (br d, J=8.4 Hz, 1H),4.90-4.97 (m, 1H), 3.75-3.90 (m, 3H), 2.99-3.15 (m, 2H), 2.46-2.56 (m,1H), 2.21-2.31 (m, 1H), 1.90-2.02 (m, 1H), 1.77-1.89 (m, 1H).

Step 4. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-{trans-2-[2-(trifluoromethyl)phenoxy]cyclobutyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,trifluoroacetate salt (1)

A mixture of P1 (35 mg, 0.13 mmol), C9 (39 mg, 0.14 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 149 mg, 0.392 mmol) andN,N-diisopropylethylamine (0.89 mL, 0.51 mmol) in dichloromethane (2.3mL) was stirred for 20 hours. Water (5 mL) was added, and the mixturewas extracted with dichloromethane (3×5 mL). The combined organic layerswere dried over magnesium sulfate, filtered, and concentrated in vacuo.Purification was carried out using reversed phase HPLC (Column: WatersSunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water(v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v);Gradient: 10% to 100% B). Yield: 50 mg, 0.11 mmol, 85%. LCMS m/z 459.1(M+1). Retention time: 2.53 minutes (Column: Waters Atlantis dC18,4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water(v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v);Gradient: 5% to 95% B over 4.0 minutes, linear; Flow rate: 2 mL/minute).

Example 27-(4-Methyl-1H-imidazol-1-yl)-2-{trans-2-[2-(trifluoromethyl)phenoxy]cyclopentyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(2)

Step 1. Synthesis of trans-2-(dibenzylamino)cyclopentanol (C10)

To a solution of trans-2-aminocyclopentanol hydrochloride (385 mg, 2.82mmol) in 1,2-dichloroethane was added benzaldehyde (748 mg, 7.04 mmol)and triethylamine (0.51 mL, 3.7 mmol). The mixture was heated to refluxfor 2 hours, cooled to room temperature, and sodiumtriacetoxyborohydride was added. The reaction mixture was heated atreflux for an additional 18 hours, cooled to room temperature, thentaken up in dichloromethane. The organic layer was washed with saturatedaqueous sodium bicarbonate solution and with water, then dried overmagnesium sulfate, filtered, and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 25% to 50% ethyl acetate inheptane) afforded the title compound as a golden oil. Yield: 734 mg,2.61 mmol, 93%. LCMS m/z 282.2 (M+1). ¹H NMR (400 MHz, CDCl₃) δ7.35-7.39 (m, 4H), 7.32 (br dd, J=7.8, 7.2 Hz, 4H), 7.21-7.26 (m, 2H),4.05-4.12 (m, 1H), 3.79 (d, J=13.9 Hz, 2H), 3.52 (d, J=13.9 Hz, 2H),2.90-2.99 (m, 1H), 1.74-1.95 (m, 2H), 1.52-1.71 (m, 3H), 1.39-1.49 (m,1H).

Step 2. Synthesis oftrans-N,N-dibenzyl-2-[2-(trifluoromethyl)phenoxy]cyclopentanamine (C11)

To a solution of C10 (820 mg, 2.91 mmol) in tetrahydrofuran (20 mL) in ahigh pressure tube was added sodium hydride (60% in oil, 175 mg, 4.37mmol). After 15 minutes, 1-fluoro-2-(trifluoromethyl)benzene (1.43 g,8.74 mmol) was introduced, the tube was sealed, and the mixture washeated to 70° C. for 18 hours, whereupon it was cooled to roomtemperature. The mixture was taken up in ethyl acetate, then washed withwater and with saturated aqueous sodium chloride solution; the organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. Purification via silica gel chromatography (Gradient: 20% to 40%ethyl acetate in heptane) afforded the title compound as a golden oil.Yield: 212 mg, 0.498 mmol, 17%. LCMS m/z 426.2 (M+1). ¹H NMR (400 MHz,CDCl₃) δ 7.55 (d, J=7.8 Hz, 1H), 7.41 (dd, J=8.0, 7.8 Hz, 1H), 7.34-7.39(m, 4H), 7.24-7.30 (m, 4H), 7.17-7.23 (m, 2H), 7.03 (d, J=8.4 Hz, 1H),6.95 (dd, J=7.6, 7.6 Hz, 1H), 4.76-4.82 (m, 1H), 3.68 (AB quartet,J_(AB)=14.0 Hz, Δν_(AB)=41.1 Hz, 4H), 3.50-3.57 (m, 1H), 1.85-2.00 (m,2H), 1.62-1.84 (m, 4H).

Step 3. Synthesis oftrans-2-[2-(trifluoromethyl)phenoxy]cyclopentanamine, hydrochloride salt(C12)

A solution of C11 (212 mg, 0.498 mmol), hydrogen chloride (4 N in1,4-dioxane, 2 mL) and 10% Pd/C (100 mg) in methanol (5 mL) washydrogenated at 50 psi in a Parr shaker at 50° C. After 3 hours, thereaction was filtered through Celite and concentrated in vacuo to affordthe title compound as a dark residue. Yield: 156 mg, quantitative. LCMSm/z 246.2 (M+1).

Step 4. Synthesis oftrans-N-(2-chloroethyl)-2-[2-(trifluoromethyl)phenoxy]cyclopentanamine,hydrochloride salt (C13)

To a solution of C12 (130 mg, 0.463 mmol), triethylamine (0.097 mL,0.695 mmol), and sodium triacetoxyborohydride (238 mg, 1.06 mmol) inmethanol (5 mL) was added chloroacetaldehyde (55% solution in water,0.071 mL, 0.60 mmol). After 3 hours, the reaction mixture wasconcentrated in vacuo. The residue was taken up in dichloromethane andwashed with saturated aqueous sodium bicarbonate solution and withwater. The organic layer was dried over magnesium sulfate and filtered.To the filtrate was added hydrogen chloride (2 N in diethyl ether, 2 mL)and the mixture was concentrated in vacuo to afford the title compoundas a light brown solid. This material was taken on to the next stepwithout further purification. Yield: 111 mg, 0.323 mmol, 70%. LCMS m/z308.1 (M+1).

Step 5. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-{trans-2-[2-(trifluoromethyl)phenoxy]cyclopentyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(2)

To a solution of P1 (80 mg, 0.27 mmol) and C13 (110 mg, 0.32 mmol) indichloromethane (5 mL) was added N,N-diisopropylethylamine (0.19 mL,1.07 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 97%, 124 mg, 0.32 mmol). The reaction wasstirred for 5 days, then taken up in additional dichloromethane andwashed with saturated aqueous sodium bicarbonate solution and withwater. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification by reversed phase HPLC (Column:Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide inwater (VA/); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile(v/v); Gradient: 30% to 70% B) afforded the title compound as an oil.Yield: 3.6 mg, 7.6 μmol, 3%. LCMS m/z 473.3 (M+1). Retention time: 2.62minutes (Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A:0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95% B over4.0 minutes, linear; Flow rate: 2 mL/minute).

Example 32-{trans-2-[(6,7-Difluoronaphthalen-1-yl)oxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(3)

Step 1. Synthesis of 2-{[cis-2-(benzyloxy)cyclobutyl]amino}ethanol (C14)

A solution of 2-(benzyloxy)cyclobutanone (prepared according to themethod of P. Bisel et al., Eur. J. Org. Chem. 1998, 4, 729-733; 2.35 g,13.3 mmol) and 2-aminoethanol (1.63 g, 26.7 mmol) in dichloromethane (47mL) was treated with acetic acid (0.76 mL, 13.3 mmol) and sodiumtriacetoxyborohydride (5.95 g, 26.7 mmol) and stirred at roomtemperature for 16 hours. Aqueous sodium hydroxide solution (1 N, 100mL) was added and the mixture was extracted with dichloromethane (2×100mL). The combined organic layers were washed with aqueous sodiumhydroxide solution (1 N, 100 mL), dried over magnesium sulfate andconcentrated in vacuo to afford the product as a colorless oil. Yield:2.9 g, 13 mmol, 98%. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.39 (m, 5H), 4.51(AB quartet, J_(AB)=11.7 Hz, Δν_(AB)=61.1 Hz, 2H), 4.13-4.18 (m, 1H),3.54-3.58 (m, 2H), 3.32-3.39 (m, 1H), 2.72-2.78 (m, 2H), 2.5 (v br s,2H), 2.05-2.14 (m, 1H), 1.83-1.98 (m, 3H).

Step 2: Synthesis of2-[cis-2-(benzyloxy)cyclobutyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C15)

Compound P1 (2.40 g, 8.00 mmol) and C14 (2.00 g, 9.04 mmol) werecombined in dichloromethane (160 mL) and treated withN,N-diisopropylethylamine (6.06 mL, 34.8 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 97%, 7.84 g, 20.0 mmol). The reaction wasstirred at room temperature for 55 hours. Water (200 mL) was added, andthe mixture was extracted with dichloromethane (3×150 mL). The combinedorganic layers were dried over magnesium sulfate and concentrated invacuo. Purification via silica gel chromatography (Gradient: 50% to 100%[10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate)afforded the title compound as a light yellow solid. Yield: 2.95 g, 7.29mmol, 91%. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 8.35 (d,J=1.4 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.23-7.35 (m, 6H), 7.18-7.20 (m,1H), 5.22-5.29 (m, 1H), 4.45 (AB quartet, J_(AB)=11.7 Hz, Δν_(AB)=52.2Hz, 2H), 4.06-4.18 (m, 2H), 3.68-3.79 (m, 2H), 2.46-2.58 (m, 1H), 2.31(d, J=0.8 Hz, 3H).

Step 3: Synthesis of2-[cis-2-hydroxycyclobutyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C16)

Compound C15 (2.50 g, 6.18 mmol) was mixed with dichloromethane (110mL), treated with methanesulfonic acid (27 mL) and stirred at roomtemperature for 1.5 hours. Aqueous sodium hydroxide (6 N) was addeduntil the pH reached 12 and then the mixture was extracted withdichloromethane (3×150 mL, then 5×50 mL). The combined organic layerswere dried over magnesium sulfate and concentrated in vacuo. Silica gelchromatography (Gradient: 50% to 100% [20% 2 N ammonia in methanol/80%ethyl acetate] in ethyl acetate) provided the title compound as a whitesolid. Yield: 1.40 g, 4.45 mmol, 72%. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d,J=1.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.03-7.05(m, 1H), 4.70-4.78 (m, 2H), 4.26-4.40 (m, 2H), 3.99 (ddd, J=13.4, 6.9,4.3 Hz, 1H), 3.68 (ddd, J=13.3, 7.8, 4.3 Hz, 1H), 2.54-2.65 (m, 1H),2.26 (d, J=0.8 Hz, 3H), 2.20-2.34 (m, 2H), 1.89-1.99 (m, 1H).

Step 4: Synthesis ofcis-2-[7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl]cyclobutylmethanesulfonate (C17)

Methanesulfonyl chloride (148 μL, 1.91 mmol) was added drop-wise to a 0°C. solution of C16 (150 mg, 0.47 mmol) and triethylamine (530 μL, 3.82mmol) in dichloromethane (15 mL), and the mixture was stirred for 20minutes. Water (50 mL) was added, and the mixture was extracted withdichloromethane (3×50 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution, dried over magnesium sulfateand concentrated in vacuo to afford the title compound as a light yellowsolid. Yield: 175 mg, 0.45 mmol, 94%. LCMS m/z 393.4 (M+1). ¹H NMR (400MHz, CDCl₃) δ 8.24 (d, J=1.2 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.24 (d,J=7.6 Hz, 1H), 7.13-7.15 (m, 1H), 5.30-5.35 (m, 1H), 5.13-5.20 (m, 1H),4.47 (ddd, half of ABXY pattern, J=14.3, 7.6, 4.1 Hz, 1H), 4.37 (ddd,half of ABXY pattern, J=14.4, 7.4, 4.0 Hz, 1H), 3.96 (ddd, J=13.3, 7.4,4.1 Hz, 1H), 3.74 (ddd, J=13.2, 7.6, 4.0 Hz, 1H), 2.99 (s, 3H),2.66-2.77 (m, 1H), 2.29 (d, J=1.0 Hz, 3H), 2.24-2.50 (m, 3H).

Step 5: Synthesis of2-{trans-2-[(6,7-difluoronaphthalen-1-yl)oxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(3)

A mixture of C17 (20 mg, 51 μmol), 6,7-difluoronaphthalen-1-ol (9.2 mg,51 μmol), and potassium carbonate (35.6 mg, 255 μmol) in dimethylsulfoxide (1.0 mL) was heated to 100° C. for 3 hours, filtered, andpurified by reversed phase HPLC (Column: Waters XBridge C18, 5 μm;Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B:0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 20% to 70% B).LCMS m/z 477.0 (M+1). Retention time: 2.58 minutes (Column: WatersAtlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroaceticacid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid inacetonitrile (v/v); Gradient: 5% to 95% B over 4.0 minutes, linear; Flowrate: 2 mL/minute).

Example 42-({3-[4-Chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(4)

Step 1: Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-(prop-2-en-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C18)

Compound P1 (2.02 g, 6.73 mmol) and 2-(prop-2-en-1-ylamino)ethanol(prepared according to the method of M. Matteucci et al., U.S. Pat.Appl. Publ. 2007, US 20070060534 A1 20070315) (681 mg, 6.73 mmol) werecombined in dichloromethane (40 mL) and N,N-diisopropylethylamine (5.86mL, 33.7 mmol) and the mixture was stirred until it became homogenous.O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 97%, 7.92 g, 20.2 mmol) was added and thereaction was stirred at room temperature for 48 hours. Aqueous sodiumhydroxide solution (1 N) was added and the mixture was extracted threetimes with 20% isopropanol in chloroform. The combined organic layerswere dried over sodium sulfate and concentrated in vacuo. Purificationwas carried out using silica gel chromatography (Gradient: 0% to 20% [2M NH₃ in methanol] in dichloromethane) followed by trituration withethyl acetate. Yield: 718 mg, 2.52 mmol, 38%. A second crop was obtainedfrom the filtrate via a second trituration. Yield: 221 mg, 0.77 mmol,11%. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=1.2 Hz, 1H), 7.47 (d, J=7.8Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.13-7.15 (m, 1H), 5.83 (ddt, J=16.8,10.5, 6.1 Hz, 1H), 5.28-5.35 (m, 2H), 4.34-4.38 (m, 2H), 4.21 (ddd,J=6.0, 1.4, 1.2 Hz, 2H), 3.63-3.67 (m, 2H), 2.30 (d, J=1.0 Hz, 3H).

Step 2: Synthesis of(E)-1-[4-chloro-3-(trifluoromethyl)phenyl]-N-hydroxymethanimine (C19)

To a solution of 4-chloro-3-(trifluoromethyl)benzaldehyde (93.9 mg, 0.45mmol) in tetrahydrofuran (0.9 mL) and ethanol (0.9 mL) was addedhydroxylamine (50% in water, 0.20 mL) and the reaction was maintained atroom temperature for 36 hours. Methanol (3.0 mL) was added, the solventwas removed in vacuo, and the residue was triturated with toluene (2×1mL) to afford the title compound as a solid. Yield: 101 mg, 0.45 mmol,100%.

Step 3: Synthesis of4-chloro-N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride(C20)

To a solution of C19 (101 mg, 0.45 mmol) in N,N-dimethylformamide (1.05mL) was added N-chlorosuccinimide (0.45 M in N,N-dimethylformamide, 1.05mL, 0.47 mmol). The reaction mixture was heated to 60° C. for 3 hours,then cooled to room temperature and used directly in the following step.

Step 4: Synthesis of2-({3-[4-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(4)

A solution of C18 (0.4 M in dichloromethane, 0.375 mL, 0.15 mmol) wasadded to the crude reaction mixture from the previous step, followed byaddition of N-methylmorpholine (1.0 M in N,N-dimethylformamide, 0.60 mL,0.60 mmol), and the reaction mixture was left at room temperature for 66hours. After removal of solvents in vacuo, the residue was dissolved in1,2-dichloroethane (5.0 mL) and treated with 50% saturated aqueoussodium bicarbonate solution (4.0 mL). The aqueous layer was extractedwith 1,2-dichloroethane (4.0 mL), and the combined organic layers wereconcentrated in vacuo. Purification via reversed phase high pressureliquid chromatography (HPLC) (Column: Phenomenex Gemini C18, 5 μm;Mobile phase A: 0.1% ammonium hydroxide in water (v/v); Mobile phase B:0.1% ammonium hydroxide in methanol (v/v); Gradient: 5% to 100% B)yielded material assigned as the indicated 3,5-disubstituteddihydro-1,2-oxazole isomer on the basis of 2-dimensional NMRexperiments. This was concentrated from ethyl acetate three times toprovide the title compound as a yellow solid. Yield: 5.7 mg, 0.011 mmol,7%. LCMS m/z 505.9 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=1.2 Hz,1H), 7.87 (d, J=2.2 Hz, 1H), 7.54-7.64 (m, 2H), 7.45 (d, J=7.8 Hz, 1H),7.26 (d, J=8 Hz, 1H, assumed; partially obscured by solvent peak),7.13-7.16 (m, 1H), 5.11-5.20 (m, 1H), 4.45 (ddd, J=14.3, 7.0, 4.1 Hz,1H), 4.31 (ddd, J=14.3, 7.6, 4.3 Hz, 1H), 3.87-4.04 (m, 3H), 3.74 (dd,J=14.4, 6.7 Hz, 1H), 3.63 (dd, half of ABX pattern, J=17.5, 10.7 Hz,1H), 3.47 (dd, half of ABX pattern, J=17.6, 7.2 Hz, 1H), 2.28 (br s,3H).

Example 52-{cis-2-[4-Fluoro-2-(trifluoromethyl)phenoxy]cyclopentyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(5)

Step 1. Synthesis of trans-2[(2-hydroxyethyl)amino]cyclopentanol (C21)

A mixture of 6-oxabicyclo[3.1.0]hexane (3.00 g, 35.7 mmol) and2-aminoethanol (2.18 g, 35.7 mmol) in ethanol (15 mL) was stirred at 80°C. in a sealed tube for 16 hours. The reaction mixture was cooled toroom temperature and concentrated in vacuo. Purification using silicagel chromatography (Eluant: methanol in dichloromethane) afforded thetitle compound. Yield: 1.6 g, 11 mmol, 31%. ¹H NMR (400 MHz, DMSO-d₆) δ4.43-4.64 (br m, 2H), 3.68-3.75 (m, 1H), 3.44 (t, J=5.6 Hz, 2H),2.71-2.77 (m, 1H), 2.58-2.63 (m, 2H), 1.73-1.89 (m, 2H), 1.47-1.64 (m,2H), 1.34-1.44 (m, 1H), 1.17-1.28 (m, 1H).

Step 2. Synthesis of2-[trans-2-hydroxycyclopentyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C22)

The reaction of C21 with P1 was carried out according to the generalprocedure for the synthesis of 1 in Example 1. When the reaction wascomplete as assessed by thin layer chromatography, the reaction mixturewas diluted with water. The aqueous layer was extracted three times with5% methanol in dichloromethane, and the combined organic layers weredried over sodium sulfate and concentrated in vacuo. Silica gelchromatography (Eluant: methanol in dichloromethane) and triturationwith ethyl acetate afforded the title compound as an off-white solid.Yield: 340 mg, 1.04 mmol, 22%. LCMS m/z 329.0 (M+1). ¹H NMR (300 MHz,DMSO-d₆) δ 8.27 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.42 (s, 1H), 7.08 (d,J=7.3 Hz, 1H), 4.85-4.98 (br m, 1H), 4.44-4.60 (m, 1H), 4.03-4.36 (m,3H), 3.59-3.68 (m, 2H), 2.15 (s, 3H), 1.42-1.96 (m, 6H).

Step 3. Synthesis of2-{cis-2-[4-fluoro-2-(trifluoromethyl)phenoxy]cyclopentyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(5)

Triphenylphosphine (12.2 mg, 0.046 mmol) was added to a solution of C22(11 mg, 0.033 mmol) and 4-fluoro-2-(trifluoromethyl)phenol (7.4 mg,0.041 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture wastreated with a solution of diisopropyl azodicarboxylate (94%, 0.015 mL,0.071 mmol) in tetrahydrofuran, and heated at 50° C. for 18 hours, thenat 90° C. for 4 hours. The same quantities of triphenylphosphine anddiisopropyl azodicarboxylate were again added, and heating was continuedat 90° C. for an additional 4 days. The mixture was concentrated invacuo. Purification by reversed phase HPLC (Column: Waters XBridge C18,5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobilephase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 40%to 100% B) afforded the title compound. Yield: 2.8 mg, 5.7 μmol, 17%.LCMS m/z 491.1 (M+1). Retention time: 2.32 minutes (Column: WatersAtlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroaceticacid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid inacetonitrile (v/v); Gradient: 5% to 95% B over 4.0 minutes, linear; Flowrate: 2 mL/minute).

Example 67-(4-Methyl-1H-imidazol-1-yl)-2-({(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(6)

Step 1. Synthesis of(5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)furan-2(5H)-one (C23)

Imidazole (1.22 g, 17.6 mmol) and tert-butyl(diphenyl)silyl chloride(3.95 mL, 15.4 mmol) were added to a solution of(5S)-5-(hydroxymethyl)furan-2(5H)-one (1.60 g, 14.0 mmol) inN,N-dimethylformamide (50 mL), and the reaction mixture was stirred atroom temperature for 18 hours. It was then partitioned betweentert-butyl methyl ether and water; the organic layer was washed twicewith water, dried over magnesium sulfate, filtered, and concentrated invacuo. Silica gel chromatography (Gradient: 5% to 30% ethyl acetate inheptane) afforded the product as a white solid. Yield: 5.20 g,quantitative. ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.66 (m, 4H), 7.38-7.49 (m,7H), 6.19 (dd, J=5.7, 2.0 Hz, 1H), 5.06-5.10 (m, 1H), 3.93 (dd, half ofABX pattern, J=10.9, 4.5 Hz, 1H), 3.88 (dd, half of ABX pattern, J=10.8,5.0 Hz, 1H), 1.05 (s, 9H).

Step 2. Synthesis of(4S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyldihydrofuran-2(3H)-one(C24)

Copper(I) bromide-dimethyl sulfide complex (99%, 3.65 g, 17.6 mmol) wassuspended in diethyl ether (25 mL) and cooled to 0° C. After drop-wiseaddition of methyllithium (1.6 M solution in diethyl ether, 22.0 mL,35.2 mmol), the reaction mixture was cooled to −25° C. A solution of C23(3.10 g, 8.79 mmol) in diethyl ether (20 mL) was added at a rate suchthat the reaction temperature remained below −20° C. After 30 minutes,the reaction was quenched with saturated aqueous ammonium chloridesolution (50 mL) and warmed to room temperature. The mixture wasextracted with diethyl ether, and the combined organic layers were driedover magnesium sulfate, filtered, and concentrated under reducedpressure to afford the product as a thick oil, which was used in thefollowing step without additional purification. Yield: 3.20 g, 8.68mmol, 99%. ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.69 (m, 4H), 7.38-7.48 (m,6H), 4.09-4.13 (m, 1H), 3.87 (dd, half of ABX pattern, J=11.5, 3.3 Hz,1H), 3.73 (dd, half of ABX pattern, J=11.5, 3.5 Hz, 1H), 2.83 (dd,J=17.6, 8.8 Hz, 1H), 2.53-2.64 (m, 1H), 2.18 (dd, J=17.4, 7.0 Hz, 1H),1.14 (d, J=7.0 Hz, 3H), 1.06 (s, 9H).

Step 3. Synthesis of(4S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-ol(C25)

Finely ground cerium chloride (95%, 6.98 g, 26.9 mmol) was heated at135° C. under high vacuum for 2 hours, and then cooled to roomtemperature. To this material was added a solution of C24 (3.20 g, 8.68mmol) in tetrahydrofuran (40 mL); the resulting mixture was stirred for1 hour and then cooled to an internal temperature of −45° C.[4-(Trifluoromethyl)phenyl]magnesium bromide (0.48 M solution intetrahydrofuran, 54.3 mL, 26.1 mmol) was added at a rate that maintainedthe reaction temperature below −40° C., and stirring was continued for 1hour. The reaction was quenched with saturated aqueous ammonium chloridesolution (30 mL) and filtered through Celite. The filtrate was extractedwith tert-butyl methyl ether, and the combined organic layers werewashed with saturated aqueous sodium chloride solution, dried oversodium sulfate, filtered and concentrated in vacuo. The product,obtained as an oil, was used without additional purification. Yield: 4.4g, 8.6 mmol, 99%.

Step 4. Synthesis oftert-butyl({(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methoxy)diphenylsilane(C26)

Compound C25 (4.4 g, 8.6 mmol) was dissolved in dichloromethane (50 mL)and cooled to −78° C. Triethylsilane (98%, 6.97 mL, 42.8 mmol) wasadded, followed by drop-wise addition of boron trifluoride diethyletherate (98%, 5.50 mL, 42.7 mmol). After 1 hour at −78° C., thereaction was quenched with saturated aqueous sodium bicarbonatesolution, warmed to room temperature, and extracted with tert-butylmethyl ether. The combined organic layers were dried over magnesiumsulfate, filtered, combined with the product of an identical reactioncarried out on 2.5 g (4.9 mmol) of C25, and concentrated in vacuo. Twochromatographic purifications on silica gel [1) Gradient: 0% to 2.5%ethyl acetate in heptane; 2) Eluent: 1% ethyl acetate in heptane]afforded the product (the second-eluting isomer from the column) as anoil. Yield: 1.19 g, 2.39 mmol, 18%. The indicated relativestereochemistry was assigned on the basis of ¹H NMR studies carried outon the product of the following step. Products of related reactions(vide infra) were assigned corresponding stereochemistry. ¹H NMR (400MHz, CDCl₃) δ 7.70-7.75 (m, 4H), 7.51 (s, 4H), 7.36-7.48 (m, 6H), 5.10(dd, J=7.0, 6.8 Hz, 1H), 3.91 (dd, half of ABX pattern, J=10.9, 4.1 Hz,1H), 3.80 (dd, half of ABX pattern, J=10.9, 4.3 Hz, 1H), 3.72 (ddd,J=7.1, 4.1, 4.0 Hz, 1H), 2.29-2.41 (m, 1H), 1.97-2.09 (m, 2H), 1.09 (s,9H), 1.07 (d, J=6.8 Hz, 3H).

Step 5. Synthesis of{(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol(C27)

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 2.62 mL,2.62 mmol) was added to a solution of C26 (1.19 g, 2.39 mmol) intetrahydrofuran (15 mL). After 1 hour at room temperature, tert-butylmethyl ether was added, and the mixture was washed with water, driedover sodium sulfate, filtered, and concentrated in vacuo. Chromatographyon silica gel (Gradient: 10% to 50% ethyl acetate in heptane) providedthe product as a colorless oil. Yield: 530 mg, 2.04 mmol, 85%. Theindicated relative stereochemistry was supported by NOE studies on C27and its aryl stereoisomer, which was obtained in the same way from thefirst-eluting isomer of the previous step. ¹H NMR (400 MHz, CDCl₃) δ7.60 (br d, J=8.0 Hz, 2H), 7.44-7.49 (m, 2H), 5.09 (dd, J=7.2, 7.0 Hz,1H), 3.84-3.91 (m, 1H), 3.67-3.75 (m, 2H), 2.16-2.27 (m, 1H), 2.05-2.10(m, 2H), 1.90 (br s, 1H), 1.13 (d, J=6.8 Hz, 3H).

Step 6. Synthesis of{(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methylmethanesulfonate (C28)

The product, obtained as an oil, was prepared from C27 according to thegeneral procedure for the synthesis of C8 in Example 1. Yield: 689 mg,2.04 mmol, 100%. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (br d, J=8.1 Hz, 2H),7.45-7.49 (m, 2H), 5.13 (br dd, J=7.1, 6.9 Hz, 1H), 4.43 (dd, half ofABX pattern, J=11.0, 3.4 Hz, 1H), 4.37 (dd, half of ABX pattern, J=11.0,5.6 Hz, 1H), 3.90 (ddd, J=7.2, 5.6, 3.3 Hz, 1H), 3.07 (s, 3H), 2.18-2.30(m, 1H), 2.07-2.12 (m, 2H), 1.17 (d, J=6.8 Hz, 3H).

Step 7. Synthesis of2-[({(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol(C29)

Compound C28 (689 mg, 2.04 mmol) was combined with 2-aminoethanol (96%,2 mL, 30 mmol) and heated to 85° C. for 2 hours. After cooling to roomtemperature, the reaction mixture was partitioned between tert-butylmethyl ether and water (10 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to provide the product as athick oil. Yield: 618 mg, 2.04 mmol, 100%. LCMS m/z 304.2 [M+H⁺]. ¹H NMR(400 MHz, CDCl₃) δ 7.59 (br d, J=8 Hz, 2H), 7.42-7.47 (m, 2H), 5.05 (brdd, J=6.8, 6.6 Hz, 1H), 3.69-3.75 (m, 1H), 3.67 (t, J=5.3 Hz, 2H),2.79-2.94 (m, 4H), 2.01-2.12 (m, 3H), 1.11 (d, J=6.2 Hz, 3H).

Step 8. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(6)

To a solution of P2 (514 mg, 2.01 mmol) and C29 (610 mg, 2.01 mmol) indichloromethane (20 mL) was added N,N-diisopropylethylamine (1.23 mL,7.06 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 99%, 1.78 g, 4.63 mmol). The reaction mixturewas heated at reflux for 2 hours, then diluted with additionaldichloromethane and washed with saturated aqueous sodium bicarbonatesolution, with water, and with saturated aqueous sodium chloridesolution. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified via silica gelchromatography (Gradient: 0% to 5% [˜0.7 M ammonia in methanol] in ethylacetate). The off-white foam obtained from the column was treated withethyl acetate; after standing, a precipitate formed. This was isolatedby filtration and washed with small amounts of ethyl acetate andtert-butyl methyl ether to afford the product as a white solid. Yield:243 mg, 0.499 mmol, 25%. LCMS m/z 487.3 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃)δ 8.33 (d, J=1.3 Hz, 1H), 7.62 (br d, J=8.1 Hz, 2H), 7.49 (d, J=7.7 Hz,1H), 7.43 (br d, J=8 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H), 7.15-7.17 (m, 1H),5.04 (br dd, J=7, 7 Hz, 1H), 4.40 (ddd, half of ABXY pattern, J=14.2,7.2, 4.2 Hz, 1H), 4.30 (ddd, half of ABXY pattern, J=14.2, 7.7, 4.2 Hz,1H), 4.22 (dd, J=14.0, 2.5 Hz, 1H), 3.99 (ddd, J=13.5, 7.9, 4.2 Hz, 1H),3.79-3.87 (m, 2H), 3.46 (dd, J=14.0, 8.0 Hz, 1H), 2.32 (d, J=1.0 Hz,3H), 2.06-2.11 (m, 3H), 1.19-1.22 (m, 3H).

Example 72-({(2S,4R,5S)-4-Fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(7)

Step 1. Synthesis of(5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)dihydrofuran-2(3H)-one(C30)

(5S)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one was converted to theproduct according to the general procedure for the synthesis of C23 inExample 6. In this case, the crude product was recrystallized fromhexanes, and the product was obtained as a white solid. Yield: 10.6 g,29.9 mmol, 56%. ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.69 (m, 4H), 7.38-7.48(m, 6H), 4.58-4.64 (m, 1H), 3.89 (dd, half of ABX pattern, J=11.3, 3.3Hz, 1H), 3.70 (dd, half of ABX pattern, J=11.3, 3.3 Hz, 1H), 2.69 (ddd,half of ABXY pattern, J=17.7, 10.2, 7.1 Hz, 1H), 2.52 (ddd, half of ABXYpattern, J=17.8, 10.0, 6.6 Hz, 1H), 2.18-2.35 (m, 2H), 1.07 (s, 9H).

Step 2. Synthesis of(3R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorodihydrofuran-2(3H)-one(C31)

A solution of C30 (5.00 g, 14.1 mmol) andN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (4.45 g, 14.1 mmol) intetrahydrofuran (50 mL) was cooled to −78° C. Lithiumbis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 14.1 mL,14.1 mmol) was added drop-wise over 15 minutes, and the reaction mixturewas stirred at −78° C. for 2 hours. The reaction was quenched withsaturated aqueous ammonium chloride solution (15 mL), warmed to roomtemperature, and partitioned between tert-butyl methyl ether andsaturated aqueous sodium bicarbonate solution. The organic layer waswashed with saturated aqueous sodium bicarbonate solution and withsaturated aqueous sodium chloride solution, then dried over magnesiumsulfate, filtered, and concentrated in vacuo. After purification viasilica gel chromatography (Gradient: 5% to 30% ethyl acetate inheptane), recrystallization from hexanes afforded the product as a whitesolid. Yield: 1.64 g, 4.40 mmol, 31%. ¹H NMR (400 MHz, CDCl₃) δ7.61-7.66 (m, 4H), 7.39-7.50 (m, 6H), 5.50 (ddd, J=52.7, 8.6, 7.6 Hz,1H), 4.69-4.74 (m, 1H), 3.93 (ddd, J=11.6, 2.2, 2.2 Hz, 1H), 3.62 (dd,J=11.5, 2.0 Hz, 1H), 2.71 (dddd, J=13.6, 9.4, 8.6, 2.4 Hz, 1H), 2.55(dddd, J=27.7, 13.6, 8.8, 7.7 Hz, 1H), 1.06 (s, 9H).

Step 3. Synthesis of(3R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluoro-2-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-ol(C32)

Compound C31 was converted to the product according to the generalprocedure for the synthesis of C25 in Example 6. The product wasobtained as an oil, which was taken directly to the following step.Yield: 2.20 g, 4.24 mmol, 99%.

Step 4. Synthesis oftert-butyl({(2S,4R,5S)-4-fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methoxy)diphenylsilane(C33)

The product was prepared from C32 using the general procedure forsynthesis of C26 in Example 6. In this case, purification was carriedout using silica gel chromatography (Gradient: 0% to 5% ethyl acetate inheptane). Yield: 890 mg, 1.77 mmol, 42%. The indicated relativestereochemistry was consistent with NOE studies carried out on theproduct. ¹H NMR (400 MHz, CDCl₃) δ 7.69-7.74 (m, 4H), 7.58-7.62 (m, 2H),7.53 (br d, half of br AB quartet, J=8 Hz, 2H), 7.37-7.49 (m, 6H), 5.22(br d, J=26.6 Hz, 1H), 4.93-5.11 (m, 1H), 4.43-4.50 (m, 1H), 4.10 (dd,J=11.4, 3.2 Hz, 1H), 3.84 (dd, J=11.3, 3.5 Hz, 1H), 2.08-2.32 (m, 2H),1.11 (s, 9H).

Step 5. Synthesis of{(2S,4R,5S)-4-fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol(C34)

The product, obtained as a thick oil that slowly solidified, wasprepared from C33 according to the general procedure for the synthesisof C27 in Example 6. Yield: 392 mg, 1.48 mmol, 84%. The indicatedrelative stereochemistry was consistent with NOE studies carried out onthis sample. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (br d, J=8 Hz, 2H), 7.52 (brd, J=8 Hz, 2H), 5.19 (br d, J=26.8 Hz, 1H), 5.04 (dddd, J=55.0, 5.1,1.8, 1.6 Hz, 1H), 4.44-4.51 (m, 1H), 4.03 (dd, J=12.0, 2.8 Hz, 1H), 3.77(dd, J=12.0, 4.8 Hz, 1H), 2.00-2.25 (m, 2H), 1.81 (br s, 1H).

Step 6. Synthesis of{(2S,4R,5S)-4-fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methylmethanesulfonate (C35)

The product, obtained as a thick oil that slowly solidified, wasprepared from C34 using the general procedure for the synthesis of C8 inExample 1. Yield: 505 mg, 1.48 mmol, 100%. ¹H NMR (400 MHz, CDCl₃) δ7.65 (br d, J=8 Hz, 2H), 7.52 (br d, J=8 Hz, 2H), 5.25 (br d, J=26.6 Hz,1H), 4.98-5.15 (m, 1H), 4.60-4.67 (m, 1H), 4.57 (dd, half of ABXpattern, J=11.3, 2.9 Hz, 1H), 4.45 (dd, half of ABX pattern, J=11.3, 4.9Hz, 1H), 3.10 (s, 3H), 2.30 (dddd, J=19.9, 14.1, 5.2, 1.2 Hz, 1H), 2.04(dddd, J=36.8, 14.1, 10.7, 5.0 Hz, 1H).

Step 7. Synthesis of2-[({(2S,4R,5S)-4-fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol(C36)

The product, obtained as an oil, was prepared from C35 using the generalprocedure for the synthesis of C29 in Example 6. Yield: 454 mg, 1.48mmol, 100%. LCMS m/z 308.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (br d,J=8 Hz, 2H), 7.49 (br d, J=8 Hz, 2H), 5.16 (br d, J=27.3 Hz, 1H),4.93-5.10 (m, 1H), 4.44-4.52 (m, 1H), 3.69 (dd, J=5.7, 4.9 Hz, 2H), 3.01(dd, half of ABX pattern, J=12.5, 3.5 Hz, 1H), 2.84-2.96 (m, 3H), 2.24(dddd, J=21.1, 14.1, 5.0, 1.2 Hz, 1H), 1.90 (dddd, J=37.1, 14.0, 10.8,5.3 Hz, 1H).

Step 8. Synthesis of2-({(2S,4R,5S)-4-fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(7)

Compound C36 was converted to the product according to the generalmethod described for synthesis of 6 in Example 6. The product wasobtained as a solid. Yield: 50 mg, 0.10 mmol, 7%. LCMS m/z 491.3 [M+H⁺].¹H NMR (400 MHz, CDCl₃) δ 8.39 (br s, 1H), 7.67 (br d, J=8 Hz, 2H), 7.51(d, J=7.8 Hz, 1H), 7.48 (br d, J=8 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H),7.16-7.18 (m, 1H), 5.17 (br d, J=27.3 Hz, 1H), 5.04 (br dd, J=55, 5 Hz,1H), 4.57-4.65 (m, 1H), 4.32-4.47 (m, 2H), 4.30 (dd, J=14.2, 2.7 Hz,1H), 4.02 (ddd, J=13.5, 7.6, 4.1 Hz, 1H), 3.85 (ddd, J=13.5, 7.2, 4.1Hz, 1H), 3.53 (dd, J=14.1, 8.2 Hz, 1H), 2.33 (d, J=1.0 Hz, 3H),2.32-2.43 (m, 1H), 1.77-1.95 (m, 1H).

Example 87-(4-Methyl-1H-imidazol-1-yl)-2-[(1S)-1-{(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(8)

Step 1. Synthesis of (2S,3S)-2-(dibenzylamino)hex-5-yn-3-ol (C38)

n-Butyllithium (2.5 M solution in hexanes, 131 mL, 328 mmol) was addeddrop-wise over approximately 9 minutes to a −70° C. solution ofethynyl(trimethyl)silane (46.3 mL, 328 mmol) in tetrahydrofuran (1 L),and the reaction mixture was stirred at −70° C. for 30 minutes. Asolution of (1S)—N,N-dibenzyl-1-[(2R)-oxiran-2-yl]ethanamine (C37, seeJ. Barluenga et al., J. Org. Chem. 1995, 60, 6696-6699) (79.6 g, 298mmol) in tetrahydrofuran (250 mL) was added; the reaction mixture, whichhad warmed as a result of the addition, was recooled to approximately−65° C., and boron trifluoride diethyl etherate (37.6 mL, 298 mmol) wasadded. The reaction mixture was then stirred for 1.5 hours at −70° C.Saturated aqueous ammonium chloride solution (200 mL) was added, and themixture was allowed to warm to room temperature. The organic layer waswashed with saturated aqueous sodium chloride solution, and the aqueouslayer from the quenched reaction was extracted with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was dissolved in methanol (500 mL),treated with potassium carbonate (206 g, 1.49 mol) and stirred at roomtemperature for 18 hours. After filtration through Celite and rinsingwith ethyl acetate, the crude product solution was concentrated invacuo, dissolved in diethyl ether (1 L), washed with water (250 mL) andwith saturated aqueous sodium chloride solution (75 mL), dried overmagnesium sulfate, filtered and concentrated under reduced pressure.After seeding with a small sample of solid product, heptane (60 mL) wasadded, and the mixture was vigorously stirred for 5 minutes, thenfiltered; the isolated solid was rinsed with heptane (50 mL) to affordthe product as a pale orange solid. Yield: 37.3 g, 127 mmol, 43%. ¹H NMR(400 MHz, CDCl₃) δ 7.22-7.36 (m, 10H), 4.53 (s, 1H), 3.84 (d, J=13.1 Hz,2H), 3.63 (ddd, J=9.5, 5.8, 4.0 Hz, 1H), 3.34 (d, J=13.3 Hz, 2H), 2.80(dq, J=9.4, 6.6 Hz, 1H), 2.46 (ddd, half of ABXY pattern, J=17.0, 4.0,2.6 Hz, 1H), 2.21 (ddd, half of ABXY pattern, J=17.0, 6.0, 2.6 Hz, 1H),1.86 (dd, J=2.7, 2.5 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H).

Step 2. Synthesis of(2S,3S)-2-(dibenzylamino)-6-[4-(trifluoromethyl)phenyl]hex-5-yn-3-ol(C39)

Compound C38 (25.6 g, 87.2 mmol) was added to a mixture of1-bromo-4-(trifluoromethyl)benzene (12.2 mL, 87.1 mmol),tetrakis(triphenylphosphine)palladium(0) (5.04 g, 4.36 mmol) andcopper(I) iodide (997 mg, 5.24 mmol) in triethylamine (previouslydegassed with nitrogen via a dispersion tube for 20 minutes, 250 mL) andthe reaction mixture was stirred at 75° C. for 1.75 hours. After coolingto room temperature, the reaction mixture was filtered through Celiteand the filter pad was rinsed with diethyl ether (300 mL). The filtratewas poured into saturated aqueous ammonium chloride solution (250 mL);the aqueous layer was extracted with diethyl ether (250 mL), and thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Heptane (150 mL) was added to the residue, andthe mixture was again concentrated under reduced pressure. This materialwas combined with the corresponding solids from a similar reactioncarried out on C38 (25.0 g, 85.2 mmol) and purified via silica gelchromatography (Eluent: 25% ethyl acetate in heptane). The isolatedsolid (˜60 g) was recrystallized from heptane (250 mL) to afford theproduct as a reddish-brown solid. Yield: 47.2 g, 108 mmol, 63%. ¹H NMR(400 MHz, CDCl₃) δ 7.49 (br d, J=8 Hz, 2H), 7.20-7.33 (m, 12H), 4.55 (brs, 1H), 3.87 (d, J=13.1 Hz, 2H), 3.70-3.76 (m, 1H), 3.36 (d, J=13.3 Hz,2H), 2.93 (dq, J=9.4, 6.7 Hz, 1H), 2.76 (dd, half of ABX pattern,J=17.4, 3.9 Hz, 1H), 2.48 (dd, half of ABX pattern, J=17.3, 5.0 Hz, 1H),1.12 (d, J=6.7 Hz, 3H).

Step 3. Synthesis of(1S)—N,N-dibenzyl-1-{(2S)-5-[4-(trifluoromethyl)phenyl]-2,3-dihydrofuran-2-yl}ethanamine(C40)

Trifluoroacetic acid (18 mL, 230 mmol) anddi-μ-chlorodichlorobis(ethylene)diplatinum(II) (97%, 3.76 g, 6.20 mmol)were added to a solution of C39 (49.4 g, 113 mmol) in dichloromethane(80 mL). After 1.5 hours at room temperature, the reaction mixture waspoured into aqueous sodium hydroxide solution (0.5 M, 500 mL), and theaqueous layer was extracted with dichloromethane (250 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was combined with crude product froma similar reaction run on C39 (10.0 g, 22.9 mmol) and rapidly purifiedon a short column by silica gel chromatography (Eluent: 2% ethyl acetatein heptane), providing the product as a light yellow-orange solid.Yield: 46.5 g, 106 mmol, 78%. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (br ABquartet, J_(AB)=8.2 Hz, Δν_(AB)=40.1 Hz, 4H), 7.40 (br d, J=8 Hz, 4H),7.23-7.28 (m, 4H), 7.16-7.22 (m, 2H), 5.46 (dd, J=2.9, 2.7 Hz, 1H), 4.80(ddd, J=9.8, 9.6, 7.2 Hz, 1H), 3.95 (d, J=13.8 Hz, 2H), 3.63 (d, J=13.8Hz, 2H), 2.96-3.04 (m, 1H), 2.73 (br dd, J=9.8, 2.5 Hz, 2H), 1.18 (d,J=6.8 Hz, 3H).

Step 4. Synthesis of(1S)-1-{(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethanamine(C41)

Palladium hydroxide on carbon (˜50% water, 10 wt % palladium, 7.1 g, 5mmol) was added to a slurry of C40 (22.0 g, 50.3 mmol) and ammoniumformate (80.2 g, 1.27 mol) in methanol (500 mL), and the reactionmixture was stirred for 2.5 hours at room temperature, then combinedwith similar reactions run on C41 (24.5 g, 56.0 mmol) and filteredthrough Celite, rinsing with methanol (1 L). The filtrate wasconcentrated in vacuo and treated with aqueous sodium hydroxide solution(0.2 M, roughly 800 mL), while keeping the pH at approximately 9. Thiswas extracted three times with ethyl acetate (0.5 L, 1 L and 0.5 L), andthe combined organic layers were washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated underreduced pressure to afford the product as a light yellow oil.Hydrogenation was assumed to have occurred on the less hindered face;the assigned stereochemistry was also supported by the IC₅₀ obtained onthe final product 8, which indicated that the tetrahydrofuran moietybore the substituents in a cis orientation (see Table 1). Yield: 26.3 g,101 mmol, 95%. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (br AB quartet, J_(AB)=8Hz, Δν_(AB)=50 Hz, 4H), 4.96 (dd, J=7.4, 7.0 Hz, 1H), 3.70-3.77 (m, 1H),2.93-3.01 (m, 1H), 2.33-2.43 (m, 1H), 2.00-2.10 (m, 1H), 1.66-1.85 (m,2H), 1.12 (d, J=6.4 Hz, 3H).

Step 5. Synthesis of1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-N-[(1S)-1-{(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-1,6-dihydropyridine-2-carboxamide(C42)

Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (97%, 27.8g, 105 mmol) was added to a solution of C41 (21.0 g, 81.0 mmol) intetrahydrofuran (800 mL), and the mixture was heated to 40° C. for 45minutes. Compound P3 (28 g, 110 mmol) was added, and the reactionmixture was heated at reflux for 2 hours, then cooled in an ice bath toapproximately 5° C. With vigorous stirring, aqueous hydrochloric acid (1N, 75 mL) was slowly added drop-wise {Caution: gas evolution does notbegin immediately!}, bringing the pH to 7-8. Aqueous sodium hydroxidesolution (1 M, 75 mL) was added, and the mixture was filtered throughCelite, rinsing with ethyl acetate (3×500 mL). The organic layer fromthe filtrate was washed with aqueous sodium hydroxide solution (1 M, 150mL), with water (250 mL), and with saturated aqueous sodium chloridesolution (100 mL), then dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting pasty solid was dried under vacuumat 50° C., then cooled, stirred with diethyl ether (300 mL) for 20minutes, and filtered to provide the product as a cream-colored solid,still containing roughly 13% diethyl ether by weight, via ¹H NMRanalysis. Corrected yield: 31.0 g, 61.4 mmol, 76%. This material wasused in the following step. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (br d, J=8.8Hz, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.58 (br AB quartet, J_(AB)=8.2 Hz,Δν_(AB)=28.5 Hz, 4H), 7.17 (d, J=7.6 Hz, 1H), 6.98-7.00 (m, 1H), 6.34(d, J=7.6 Hz, 1H), 5.00 (dd, J=7.4, 6.6 Hz, 1H), 4.34-4.41 (m, 1H),4.28-4.33 (m, 2H), 4.06-4.14 (m, 1H), 3.96-4.03 (m, 1H), 3.71-3.78 (m,1H), 2.38-2.47 (m, 1H), 2.15-2.23 (m, 1H), 2.12 (d, J=1.0 Hz, 3H),1.80-1.95 (m, 2H), 1.35 (d, J=6.6 Hz, 3H).

Step 6. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-[(1S)-1-{(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(8)

Compound C42 (from the previous step; corrected weight: 30.9 g, 61.2mmol) and triethylamine (16 mL, 110 mmol) were combined intetrahydrofuran (1 L) and cooled in an ice bath. Methanesulfonylchloride (98%, 8.5 mL, 110 mmol) was added drop-wise over 3 to 5minutes, whereupon the cooling bath was removed. The reaction mixturewas stirred at room temperature for 40 minutes, then cooled again in anice bath, treated with1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (97%, 30.2 g, 210mmol), and stirred for 2.5 hours. Ethyl acetate (500 mL) was added tothe cold reaction mixture, which was subsequently washed with water(2×500 mL). The aqueous layer was extracted with ethyl acetate (500 mL)and the combined organic layers were washed with saturated aqueoussodium chloride solution (250 mL), dried over magnesium sulfate,filtered, and concentrated in vacuo. Silica gel chromatography (Eluents:ethyl acetate, then 5% methanol in ethyl acetate) afforded fractionscontaining the product; these were concentrated to a volume of roughly500 mL and the resulting slurry was stirred under nitrogen for 18 hours.After being cooled to 7° C., the slurry was filtered to provide a whitesolid (22 g). The filtrate was concentrated under reduced pressure, andthe resulting solid was slurried with diethyl ether (70 mL) and isolatedby filtration; this material was recrystallized from ethyl acetate (60mL), cooled in ice, filtered, and rinsed with ice-cold ethyl acetate toafford a cream-colored solid (5.5 g). The two lots were combined andrecrystallized from ethyl acetate (330 mL) to afford the product as awhite solid. Yield: 24.3 g, 49.9 mmol, 82%. LCMS m/z 487.3 [M+H⁺]. ¹HNMR (400 MHz, CDCl₃) δ 8.25 (d, J=1.2 Hz, 1H), 7.58 (br d, J=8 Hz, 2H),7.47 (d, J=7.6 Hz, 1H), 7.42 (br d, J=8 Hz, 2H), 7.30 (d, J=7.6 Hz, 1H),7.12-7.14 (m, 1H), 4.92 (dd, J=7.4, 6.8 Hz, 1H), 4.82-4.90 (m, 1H),4.26-4.39 (m, 2H), 4.09-4.16 (m, 1H), 3.79 (ddd, half of ABXY pattern,J=13.3, 7.3, 4.3 Hz, 1H), 3.67 (ddd, half of ABXY pattern, J=13.3, 7.2,4.3 Hz, 1H), 2.37-2.45 (m, 1H), 2.30 (d, J=1.0 Hz, 3H), 2.15-2.24 (m,1H), 1.77-1.91 (m, 2H), 1.33 (d, J=7.0 Hz, 3H).

Example 92-[(1S)-1-{(2S,5R)-5-[4-Chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(9)

Step 1. Synthesis of tert-butyl [(2S)-4-chloro-3-oxobutan-2-yl]carbamate(C43)

A solution of chloroacetic acid (23.2 g, 246 mmol) in tetrahydrofuran(100 mL) was added over 35 minutes to a −78° C. solution of lithiumdiisopropylamide in tetrahydrofuran (2.05 M, 240 mL, 492 mmol), at arate that kept the internal temperature below −65° C. After 30 minutes,the reaction mixture was quickly transferred into a (dry ice)-jacketedaddition funnel and added over 5 minutes to a solution of methylN-(tert-butoxycarbonyl)-L-alaninate (10.0 g, 49.2 mmol) intetrahydrofuran (120 mL). Mechanical stirring was used for thisreaction. The mixture was stirred for 30 minutes, during which time thereaction mixture warmed to 0° C. It was cooled to −78° C. and treatedover 10 minutes with a solution of acetic acid (41 mL, 720 mmol) intetrahydrofuran (41 mL). At this point, the flask was immersed in an icebath, and stirring was continued for 1.5 hours, while the reactionwarmed to 5° C. Water (250 mL) was added, followed by diethyl ether (400mL); the organic layer was washed with saturated aqueous sodiumbicarbonate solution (150 mL) and with saturated aqueous sodium chloridesolution (50 mL), dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford the product as a waxy, light yellowsolid. Yield: 9.47 g, 42.7 mmol, 87%. ¹H NMR (400 MHz, CDCl₃) δ 5.11 (brd, J=6 Hz, 1H), 4.48-4.58 (m, 1H), 4.28 (AB quartet, J_(AB)=15.9 Hz,Δν_(AB)=8.3 Hz, 2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz, 3H).

Step 2. Synthesis of tert-butyl[(2S,3R)-4-chloro-3-hydroxybutan-2-yl]carbamate (C44)

A solution of C43 (16.0 g, 72.2 mmol) in diethyl ether (100 mL) wasadded to a mixture of lithium tri-tert-butoxyaluminum hydride (97%, 28.4g, 108 mmol) in diethyl ether (500 mL). After 3 hours at roomtemperature, the reaction mixture was cooled to 0° C., quenched withaqueous hydrochloric acid (1 M, 150 mL), and extracted with tert-butylmethyl ether. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo to provide a thick oil,which was stirred with methylcyclohexane (45 mL). The resulting solidwas isolated via filtration and washed with methylcyclohexane to providethe product (3.1 g). The filtrate was concentrated, mixed with pentane(25 mL), heated to reflux, cooled with stirring and seeded with solidproduct. The resulting material was filtered and rinsed with pentane toprovide the product as a solid (8.1 g). Total yield: 11.2 g, 50.1 mmol,69%. ¹H NMR (400 MHz, CDCl₃) δ 4.76 (br s, 1H), 3.77-3.87 (m, 1H),3.69-3.76 (m, 1H), 3.65 (dd, half of ABX pattern, J=11.3, 3.9 Hz, 1H),3.53 (dd, half of ABX pattern, J=11.3, 8.0 Hz, 1H), 2.95 (br s, 1H),1.45 (s, 9H), 1.27 (d, J=6.8 Hz, 3H).

Alternative Step 2. Synthesis of tert-butyl[(2S,3R)-4-chloro-3-hydroxybutan-2-yl]carbamate (C44)

A 0.1 M potassium phosphate buffer, 2.0 mM in magnesium chloride, wasprepared by combining potassium dihydrogenphosphate (9.86 g, 72.4 mmol),potassium hydrogenphosphate (22.2 g, 127 mmol) and magnesium chloridehexahydrate (0.812 g, 4.0 mmol) in water (2 L); the pH of the resultingsolution was 7.05. To this phosphate buffer (1.8 L) was addednicotinamide adenine dinucleotide phosphate, disodium salt trihydrate(1.9 g, 2.4 mmol) and ketoreductase enzyme (Codexis, KRED-P1-E05) (8 g),and the mixture was stirred for 45 minutes at 22° C. to dissolve theketoreductase. A solution of tert-butyl[(2S)-4-chloro-3-oxobutan-2-yl]carbamate (C43) (50.0 g, 226 mmol) in2-propanol (200 mL) was added, and the resulting suspension was stirredfor 46 hours at 30° C., under a nitrogen flow (10 mL/minute) from asparge inlet containing 2-propanol and water (1:1, 300 mL). At thispoint, tert-butyl methyl ether (1 L) was added to the reaction mixture,which was swirled for 20 minutes. The resulting emulsion was filteredthrough diatomaceous earth (200 g), and the filter cake was broken andwashed with tert-butyl methyl ether (3×400 mL). The combined organiclayers from the filtrates were dried with sodium sulfate (625 g),filtered, and concentrated in vacuo to afford the crude product as a redoil (50 g). This material was mixed with ethyl acetate (80 mL) andtreated with decolorizing carbon (5 g) over 10 minutes with gentleheating. After filtration through Celite, the solution was concentratedin vacuo and mixed with warm hexanes (40 mL) under stirring. After 18hours, the resulting solid was collected via filtration and rinsed withpentane, providing the product as a white powder (14.14 g). The motherliquor was concentrated under reduced pressure to yield an oil (32 g),which was crystallized in the same way using warm hexanes (30 mL) toobtain additional product as a white powder (13.65 g). Total yield:27.79 g, 124 mmol, 55%. ¹H NMR (400 MHz, CDCl₃) δ 4.77 (br s, 1H),3.77-3.87 (m, 1H), 3.69-3.76 (m, 1H), 3.65 (dd, half of ABX pattern,J=11.1, 3.9 Hz, 1H), 3.53 (dd, half of ABX pattern, J=11.3, 8.0 Hz, 1H),3.00 (br s, 1H), 1.45 (s, 9H), 1.26 (d, J=6.8 Hz, 3H).

Step 3. Synthesis of(2R,3S)-3-[(tert-butoxycarbonyl)amino]-1-chlorobutan-2-yl4-nitrobenzoate (C45)

A solution of C44 (15 g, 67 mmol) in dichloromethane (400 mL) was cooledto 0° C. and treated with triethylamine (11.7 mL, 83.9 mmol) and4-(dimethylamino)pyridine (99%, 827 mg, 6.70 mmol). A solution of4-nitrobenzoyl chloride (15.6 g, 84.1 mmol) in dichloromethane (100 mL)was then added, and the reaction mixture was allowed to slowly warm toroom temperature over 18 hours. Dichloromethane (500 mL) was added, andthe solution was washed with aqueous hydrochloric acid (1 M, 250 mL),dried over sodium sulfate, filtered and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 0% to 3% ethylacetate in dichloromethane) afforded the product as a pale yellow solid.Yield: 23 g, 62 mmol, 92%. ¹H NMR (400 MHz, CDCl₃) δ 8.24-8.34 (m, 4H),5.28-5.33 (m, 1H), 4.55 (br d, J=9 Hz, 1H), 4.19-4.30 (br m, 1H),3.71-3.87 (m, 2H), 1.38 (br s, 9H), 1.25 (d, J=6.8 Hz, 3H).

Step 4. Synthesis of tert-butyl{(1S)-1-[(2R)-oxiran-2-yl]ethyl}carbamate (C46)

An aqueous solution of potassium hydroxide (23.9 g of 85% purity, 362mmol, in 160 mL water) was added drop-wise to a 0° C. solution of C45(27 g, 72 mmol) in ethanol (1 L), and the reaction mixture was stirredfor 1 hour at 0° C. At that point, it was diluted with water (1 L) andextracted with tert-butyl methyl ether (2×500 mL). The combined organiclayers were washed with aqueous sodium hydroxide solution (1 M, 2×250mL), dried over sodium sulfate, filtered, and concentrated in vacuo.Silica gel chromatography (Gradient: 5% to 30% ethyl acetate in heptane)provided the product as a colorless oil. Yield: 11.9 g, 63.6 mmol, 88%.¹H NMR (400 MHz, CDCl₃) δ 4.41 (br s, 1H), 3.93-4.06 (br m, 1H), 2.99(ddd, J=3.9, 2.5, 2.5 Hz, 1H), 2.74 (dd, J=4.7, 4.0 Hz, 1H), 2.61 (brdd, J=4.7, 2.7 Hz, 1H), 1.44 (s, 9H), 1.27 (d, J=6.9 Hz, 3H).

Step 5. Synthesis of tert-butyl[(2S,3S)-3-hydroxy-6-(trimethylsilyl)hex-5-yn-2-yl]carbamate (C47)

n-Butyllithium (2.5 M solution in hexanes, 39.7 mL, 99 mmol) was addeddrop-wise to a −20° C. solution of ethynyl(trimethyl)silane (15 mL, 110mmol) in toluene (100 mL), at a rate that kept the reaction temperaturebelow −15° C. The reaction mixture was stirred for 15 minutes at thistemperature. Dimethylaluminum chloride (97%, 1.0 M solution in hexanes,96 mL, 96 mmol) was added, and the reaction flask was immersed in an icebath for 1 hour, then warmed to room temperature for 30 minutes. Aftercooling the reaction mixture to 0° C., a solution of C46 (6.2 g, 33mmol) in toluene (50 mL) was added, and stirring was continued at 0° C.for 1 hour, at which time the reaction mixture was warmed to roomtemperature for 1 hour and subsequently cooled to 0° C. A mixture ofsaturated aqueous citric acid (100 mL) and water (100 mL) was added, andthe ice bath was removed. tert-Butyl methyl ether (500 mL) was added,and the mixture was stirred for 15 minutes; the organic layer was thenwashed with water (100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo, providing the product as a thick oil. Yield: 7.2g, 25 mmol, 76%. ¹H NMR (400 MHz, CDCl₃) δ 4.79 (br s, 1H), 3.64-3.74(m, 2H), 2.48 (dd, half of ABX pattern, J=16.9, 7.4 Hz, 1H), 2.43 (dd,half of ABX pattern, J=16.9, 5.3 Hz, 1H), 2.36 (br s, 1H), 1.45 (s, 9H),1.24 (d, J=6.6 Hz, 3H), 0.17 (s, 9H).

Step 6. Synthesis of tert-butyl[(2S,3S)-3-hydroxyhex-5-yn-2-yl]carbamate (C48)

Potassium carbonate (6.97 g, 50.4 mmol) was added to a solution of C47(7.2 g, 25 mmol) in methanol (50 mL). After stirring at room temperaturefor 1.5 hours, the reaction mixture was partitioned between water (50mL) and tert-butyl methyl ether (400 mL). The aqueous layer wasextracted with tert-butyl methyl ether (100 mL); the combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo to give the product as a thick oil. Yield: 5.0 g, 23 mmol, 92%. ¹HNMR (400 MHz, CDCl₃) δ 4.76 (br s, 1H), 3.67-3.80 (m, 2H), 2.74 (br s,1H), 2.41-2.44 (m, 2H), 2.06 (dd, J=2.7, 2.6 Hz, 1H), 1.45 (s, 9H), 1.23(d, J=6.8 Hz, 3H).

Step 7. Synthesis of tert-butyl{(2S,3S)-6-[4-chloro-2-(trifluoromethyl)phenyl]-3-hydroxyhex-5-yn-2-yl}carbamate(C49)

Compound C48 was reacted with 4-chloro-1-iodo-2-(trifluoromethyl)benzeneusing the general method described for synthesis of C39 in Example 8,except that tert-butyl methyl ether was used in place of diethyl ether,and no recrystallization was carried out in this case. The product wasobtained as a thick oil. Yield: 19.2 g, 49.0 mmol, 100%. ¹H NMR (400MHz, CDCl₃) δ 7.63 (br d, J=2.0 Hz, 1H), 7.44-7.52 (m, 2H), 4.80 (br s,1H), 3.73-3.84 (m, 2H), 2.63-2.75 (m, 2H), 1.45 (s, 9H), 1.27 (br d,J=6.6 Hz, 3H).

Step 8. Synthesis of tert-butyl[(1S)-1-{(2S)-5-[4-chloro-2-(trifluoromethyl)phenyl]-5-methoxytetrahydrofuran-2-yl}ethyl]carbamate(C50)

p-Toluenesulfonic acid monohydrate (96%, 1.55 g, 7.82 mmol) anddi-μ-chlorodichlorobis(ethylene)diplatinum(II) (97%, 545 mg, 0.900 mmol)were added to a solution of C49 (33 g, 84 mmol) and trimethylorthoformate (40 mL, 360 mmol) in methanol (400 mL), and the reactionmixture was stirred at room temperature for 3 hours. Additionaldi-μ-chlorodichlorobis(ethylene)diplatinum(II) (97%, 500 mg, 0.82 mmol)was introduced, and stirring was continued for 3 hours. The reactionmixture was poured into saturated aqueous sodium bicarbonate solution(400 mL) and extracted with tert-butyl methyl ether; the combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford the product as a thick oil, which wastaken directly to the following reaction.

Step 9. Synthesis of tert-butyl[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]carbamate(C51)

Compound C50 from the previous step was converted to the product usingthe general method for synthesis of C26 in Example 6. In this case, thequenched reaction was extracted with dichloromethane; the combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. Silica gel chromatography (Gradient: 0% to 10%ethyl acetate in heptane) afforded a solid (41.8 g), which was dissolvedin methanol (50 mL) and treated with water (˜7 mL) until the solutionbecame cloudy. After stirring for 2 hours, the mixture was filtered, andthe isolated solid was rinsed with a 3:7 mixture of methanol and water,providing the product as a solid (6.9 g). The filtrate was concentrateduntil a precipitate formed; this was isolated via filtration to provide15 g of a solid, which was treated in the same way to provide additionalproduct as a solid (9.5 g). Total yield over 2 steps: 16.4 g, 41.6 mmol,50%. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (br d, J=8.4 Hz, 1H), 7.61 (br d,J=2.2 Hz, 1H), 7.53 (br dd, J=8.6, 2.2 Hz, 1H), 5.13 (br dd, J=8, 7 Hz,1H), 4.67 (br s, 1H), 3.84-3.94 (m, 2H), 2.32-2.42 (m, 1H), 2.01-2.11(m, 1H), 1.78-1.89 (m, 1H), 1.58-1.68 (m, 1H), 1.47 (s, 9H), 1.26 (d,J=6.5 Hz, 3H).

Step 10. Synthesis of(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethanamine(C52)

Trifluoroacetic acid (25 mL, 340 mmol) was added to a solution of C51(16.4 g, 41.6 mmol) in dichloromethane (250 mL). The reaction mixturewas stirred at room temperature for 18 hours, then poured into aqueoussodium hydroxide solution (1 M, 350 mL). Additional dichloromethane (500mL) was added, and the aqueous layer was extracted with dichloromethane(2×200 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to provide the product as a brownoil. Yield: 12 g, 41 mmol, 98%. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (br d,J=8.4 Hz, 1H), 7.60 (br d, J=2.2 Hz, 1H), 7.50-7.54 (m, 1H), 5.17-5.23(m, 1H), 3.67-3.74 (m, 1H), 3.01-3.09 (m, 1H), 2.35-2.46 (m, 1H),1.98-2.09 (m, 1H), 1.59-1.74 (m, 2H), 1.14 (d, J=6.5 Hz, 3H).

Step 11. Synthesis ofN-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C53)

Compound C52 was converted to the product using the general methodemployed for synthesis of C42 in Example 8, except that C53 was notstirred with diethyl ether. The product was obtained as an off-whitesolid. Yield: 21 g, 39 mmol, 95%. LCMS m/z 539.3 [M+H⁺]. ¹H NMR (400MHz, CDCl₃) δ 8.12 (br d, J=9 Hz, 1H), 8.00-8.02 (m, 1H), 7.89 (br d,J=8.5 Hz, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.56 (br dd, J=8.5, 2 Hz, 1H),7.22 (d, J=7.5 Hz, 1H), 7.00-7.02 (m, 1H), 6.39 (d, J=7.6 Hz, 1H), 5.22(br dd, J=8, 7 Hz, 1H), 4.36-4.46 (m, 1H), 4.27-4.31 (m, 2H), 3.93-4.07(m, 2H), 3.72-3.78 (m, 1H), 2.40-2.49 (m, 1H), 2.16-2.26 (m, 1H), 2.14(d, J=0.9 Hz, 3H), 1.7-1.9 (m, 2H), 1.36 (d, J=6.7 Hz, 3H).

Step 12. Synthesis of2-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(9)

Compound C53 was converted to the product using the general methoddescribed for synthesis of 8 in Example 8, except for the purification.In this case, after silica gel chromatography (Gradient: 0% to 5%methanol in dichloromethane), material from the chromatography wasrecrystallized from ethyl acetate to provide the product. The filtratefrom the recrystallization was concentrated, triturated with diethylether, and recrystallized from ethyl acetate to provide additionalproduct. These two lots were combined (25 g), slurried in tert-butylmethyl ether (50 mL) and warmed to 50° C. for 15 minutes. Cooling andisolation via filtration afforded the product as an off-white solid.Yield: 24.7 g, 47.4 mmol, 72%. LCMS m/z 521.3 [M+H⁺]. ¹H NMR (400 MHz,CDCl₃) δ 8.30 (br s, 1H), 7.70 (br d, J=8.4 Hz, 1H), 7.57 (br d, J=2.2Hz, 1H), 7.52 (dd, J=8.3, 2.1 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.30 (d,J=7.8 Hz, 1H), 7.12-7.14 (m, 1H), 5.14-5.20 (m, 1H), 4.93 (dq, J=9.4,6.8 Hz, 1H), 4.43 (ddd, half of ABXY pattern, J=14.1, 7.0, 3.9 Hz, 1H),4.26 (ddd, half of ABXY pattern, J=14.1, 8.0, 4.1 Hz, 1H), 4.06 (ddd,J=9.3, 7.1, 6.6 Hz, 1H), 3.74 (ddd, half of ABXY pattern, J=13.4, 8.0,4.0 Hz, 1H), 3.66 (ddd, half of ABX pattern, J=13.4, 7.1, 4.1 Hz, 1H),2.38-2.48 (m, 1H), 2.31 (d, J=1.0 Hz, 3H), 2.17-2.27 (m, 1H), 1.70-1.88(m, 2H), 1.31 (d, J=6.8 Hz, 3H).

Example 102-[(1S)-1-{(2S,5R)-5-[3,5-Difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(10)

Step 1. Synthesis of(2S,3S)-2-(dibenzylamino)-6-[3,5-difluoro-4-(trifluoromethyl)phenyl]hex-5-yn-3-ol(C54)

Compound C38 was converted to the product via reaction with5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene, using the methoddescribed for synthesis of C49 in Example 9. The product was obtained asa solid. Yield: 3.10 g, 6.55 mmol, 96%. LCMS m/z 474.2 [M+H⁺]. ¹H NMR(400 MHz, CDCl₃) δ 7.22-7.35 (m, 10H), 6.74 (d, J=10.2 Hz, 2H), 4.56 (s,1H), 3.86 (d, J=13.3 Hz, 2H), 3.68-3.76 (m, 1H), 3.34 (d, J=13.3 Hz,2H), 2.85-2.96 (m, 1H), 2.79 (dd, J=17.4, 3.7 Hz, 1H), 2.47 (dd, J=17.4,4.3 Hz, 1H), 1.11 (d, J=6.6 Hz, 3H).

Step 2. Synthesis of(1S)—N,N-dibenzyl-1-{(2S)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]-2,3-dihydrofuran-2-yl}ethanamine(C55)

Compound C54 was converted to the product using the general methoddescribed for synthesis of C40 in Example 8. In this case, the reactionwas quenched with saturated aqueous sodium bicarbonate solution ratherthan aqueous sodium hydroxide solution. The product was isolated as athick oil. Yield: 1.96 g, 4.14 mmol, 78%. LCMS m/z 474.2 [M+H⁺]. ¹H NMR(400 MHz, CDCl₃) δ 7.38 (br d, half of AB quartet, J=7.4 Hz, 4H),7.25-7.30 (m, 4H), 7.15-7.23 (m, 4H), 5.50-5.53 (m, 1H), 4.78 (ddd,J=9.8, 9.8, 7.0 Hz, 1H), 3.91 (d, J=14.0 Hz, 2H), 3.58 (d, J=13.7 Hz,2H), 2.92-3.01 (m, 1H), 2.68-2.83 (m, 2H), 1.19 (d, J=7.0 Hz, 3H).

Step 3. Synthesis of(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethanamine(C56)

The product was prepared from C55 according to the general procedure forthe synthesis of C41 in Example 8, except that tert-butyl methyl etherwas used in the work-up rather than ethyl acetate. The product wasobtained as an oil. Yield: 629 mg, 2.10 mmol, 90%. ¹H NMR (400 MHz,CDCl₃) δ 7.00 (d, J=10.2 Hz, 2H), 4.91 (dd, J=7.2, 6.8 Hz, 1H),3.70-3.77 (m, 1H), 2.93-3.01 (m, 1H), 2.34-2.44 (m, 1H), 1.99-2.09 (m,1H), 1.73-1.87 (m, 3H), 1.61-1.71 (m, 1H), 1.11 (d, J=6.6 Hz, 3H).

Step 4. Synthesis ofN-[(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C57)

Conversion of C56 to the product employed the general method describedfor synthesis of C42 in Example 8. In this case, the cooled reactionmixture was quenched with aqueous sodium hydroxide solution (1 M, 25mL), then extracted three times with ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo. The residue was triturated with tert-butyl methyl ether to affordthe product as a white solid. Yield: 730 mg, 1.35 mmol, 65%. ¹H NMR (400MHz, CDCl₃) δ 8.61 (br d, J=9 Hz, 1H), 7.96 (br s, 1H), 7.17 (d, J=7.6Hz, 1H), 7.11 (br d, J=10.3 Hz, 2H), 6.98-7.00 (m, 1H), 6.41 (d, J=7.4Hz, 1H), 4.95 (dd, J=7.2, 6.6 Hz, 1H), 4.30-4.46 (m, 3H), 4.07-4.18 (m,2H), 3.94-4.02 (m, 1H), 2.41-2.50 (m, 1H), 2.12-2.22 (m, 1H), 2.08 (brs, 3H), 1.74-1.93 (m, 2H), 1.35 (d, J=6.6 Hz, 3H).

Step 5. Synthesis of1-(2-chloroethyl)-N-[(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C58)

Thionyl chloride (1.0 mL, 14 mmol) was added to a 0° C. mixture of C57(1.00 g, 1.85 mmol) in dichloromethane (20 mL). The ice bath wasremoved, and the reaction mixture was stirred at room temperature for 2hours, then cooled to 0° C. and quenched with saturated aqueous sodiumbicarbonate solution. The aqueous layer was extracted with ethylacetate, and the combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to provide the product as a stickyyellow foam, which was taken directly to the following step. Yield: 1.00g, 1.79 mmol, 97%. LCMS m/z 559.1 [M+H⁺].

Step 6. Synthesis of2-[(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(10)

Lithium bis(trimethylsilyl)amide (1 M solution in THF, 2.24 mL, 2.24mmol) was added drop-wise to a 0° C. solution of C58 (from the precedingstep, 1.00 g, 1.79 mmol) in tetrahydrofuran (20 mL), and the reactionmixture was stirred at 0° C. for 15 minutes. The ice bath was removed,and stirring was continued for 1 hour. After cooling to 0° C., thereaction was quenched with saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Silica gelchromatography (Gradient: 0% to 20% methanol in ethyl acetate) provideda pale yellow foam (709 mg), which was recrystallized from tert-butylmethyl ether to afford the product as a white solid. Yield (two crops):404 mg, 0.773 mmol, 43%. LCMS m/z 523.3 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃)δ 8.30 (br s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H),7.13-7.15 (m, 1H), 6.98 (br d, J=10.3 Hz, 2H), 4.81-4.89 (m, 2H), 4.51(ddd, J=14.2, 6.2, 4.1 Hz, 1H), 4.21 (ddd, J=14.2, 8.2, 4.1 Hz, 1H),4.07-4.14 (m, 1H), 3.63-3.77 (m, 2H), 2.38-2.47 (m, 1H), 2.31 (s, 3H),2.17-2.26 (m, 1H), 1.76-1.92 (m, 2H), 1.31 (d, J=6.8 Hz, 3H).

Examples 11 and 127-(4-Methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(11) and7-(4-Methyl-1H-imidazol-1-yl)-2-({(2R,5S)-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(12)

Step 1. Synthesis of 2-[4-(trifluoromethyl)phenyl]hex-5-en-2-ol (C59)

A solution of hex-5-en-2-one (1.00 g, 10.2 mmol) in tetrahydrofuran (3mL) was added to [4-(trifluoromethyl)phenyl]magnesium bromide (0.26 Msolution in tetrahydrofuran, 50 mL, 13 mmol) at 0° C. After 15 minutesat 0° C., the reaction mixture was heated at 70° C. for 18 hours, thencooled to room temperature, diluted with ethyl acetate, and washed withsaturated aqueous ammonium chloride solution, with water, and withsaturated aqueous sodium chloride solution. The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 10% to 30% ethylacetate in heptane) afforded the product as a dark gold oil. Yield: 1.86g, 7.61 mmol, 75%. ¹H NMR of crude product (400 MHz, CDCl₃),characteristic peaks: δ 7.59 (br AB quartet, J_(AB)=8 Hz, Δν_(AB)=19 Hz,4H), 5.74-5.85 (m, 1H), 4.93-5.01 (m, 2H), 1.59 (s, 3H).

Step 2. Synthesis of{5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol(C60)

3-Chloroperoxybenzoic acid (70%, 3.73 g, 15.1 mmol) was added to asolution of C59 (1.85 g, 7.57 mmol) in dichloromethane (50 mL). After 3hours, the reaction mixture was washed with 10% aqueous sodium sulfitesolution, with saturated aqueous sodium bicarbonate solution, and withwater. The organic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. By ¹H NMR, this crude product contained a minoramount of the intermediate epoxide [characteristic epoxide peaks at 400MHz, in CDCl₃: 2.87-2.92 (m, 1H), 2.75 (dd, J=4.7, 4.1 Hz, 1H), 2.45(dd, J=4.9, 2.7 Hz, 1H)]. The crude product was therefore dissolved indichloromethane (30 mL), treated with p-toluenesulfonic acid monohydrate(142 mg, 0.746 mmol) and allowed to stir at room temperature for 18hours. The reaction mixture was then washed with saturated aqueoussodium bicarbonate solution and with water, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Purificationvia silica gel chromatography (Gradient: 20% to 40% ethyl acetate inheptane) provided the product as a yellow oil, which by ¹H NMR analysisconsisted of a roughly 1:1 mixture of diastereomers. Yield: 1.65 g, 6.34mmol, 84%. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 7.49-7.61(m, 4H), [4.29-4.37 (m) and 4.13-4.20 (m), total 1H], [3.78 (br dd,J=11.6, 2.4 Hz) and 3.71 (br dd, J=11.4, 2.8 Hz), total 1H], 3.54-3.64(m, 1H), 2.03-2.28 (m, 3H), 1.55 and 1.53 (2 s, total 3H).

Step 3. Synthesis of{cis-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl4-methylbenzenesulfonate (C61)

4-Methylbenzenesulfonyl chloride (98%, 1.60 g, 8.22 mmol) was added to asolution of C60 (1.65 g, 6.34 mmol) and triethylamine (1.32 mL, 9.47mmol) in dichloromethane (25 mL) at 0° C., and the reaction mixture wasallowed to slowly warm to room temperature as the ice bath melted. After18 hours, the solution was washed with saturated aqueous sodiumbicarbonate solution and with water. The organic layer was concentratedin vacuo and purified via silica gel chromatography (Gradient: 10% to40% ethyl acetate in heptane). The product, which was the more polarisomer, was obtained as a white solid. Yield: 830 mg, 2.00 mmol, 32%. ¹HNMR (400 MHz, CDCl₃) δ 7.79 (br d, J=8.4 Hz, 2H), 7.44 (br AB quartet,J_(AB)=8.2 Hz, Δν_(AB)=31.0 Hz, 4H), 7.34 (br d, J=8 Hz, 2H), 4.37-4.44(m, 1H), 4.05 (dd, half of ABX pattern, J=10.1, 4.4 Hz, 1H), 4.00 (dd,half of ABX pattern, J=10.1, 5.8 Hz, 1H), 2.47 (s, 3H), 2.08-2.22 (m,3H), 1.62-1.71 (m, 1H), 1.48 (s, 3H). Also obtained was the less polarisomer{trans-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl4-methylbenzenesulfonate (C62), as a thick, colorless gum (878 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.84 (br d, J=8.4 Hz, 2H), 7.56 (br d, J=8.5 Hz,2H), 7.44 (br d, J=8.5 Hz, 2H), 7.35-7.39 (m, 2H), 4.19-4.26 (m, 1H),4.06-4.14 (m, 2H), 2.46 (s, 3H), 2.16-2.24 (m, 1H), 2.04-2.12 (m, 1H),1.82-1.89 (m, 2H), 1.47 (s, 3H). The indicated relativestereochemistries of C61 and C62 were assigned based on NOE studies.

Step 4. Synthesis of2-[({cis-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol(C63)

A mixture of 2-aminoethanol (856 mg, 14.0 mmol) and C61 (830 mg, 2.00mmol) in acetonitrile (10 mL) was heated at 90° C. for 18 hours, thencooled to room temperature, diluted with ethyl acetate, and washed withwater and with saturated aqueous sodium chloride solution. The organiclayer was dried over magnesium sulfate, filtered, and concentrated invacuo to provide the product as a light yellow oil. Yield: 559 mg, 1.84mmol, 92%. LCMS m/z 304.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (br ABquartet, J_(AB)=8.4 Hz, Δν_(AB)=15.9 Hz, 4H), 4.29-4.37 (m, 1H), 3.65(t, J=5.3 Hz, 2H), 2.79-2.91 (m, 2H), 2.74 (d, J=5.9 Hz, 2H), 2.06-2.25(m, 3H), 1.54-1.64 (m, 1H), 1.52 (s, 3H).

Step 5. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(11) and7-(4-methyl-1H-imidazol-1-yl)-2-({(2R,5S)-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(12)

Compound C63 was converted to the products using the general methoddescribed for synthesis of 6 in Example 6. In this case, silica gelchromatography was carried out using a gradient of 0% to 20% methanol inethyl acetate. The racemic product was separated into its enantiomersvia supercritical fluid chromatography (Column: Chiralcel OJ-H, 5 μm;Eluent: 4:1 carbon dioxide/methanol containing 0.2% isopropylamine). Thefirst-eluting peak was Example 11, obtained as a solid. Yield: 47 mg, 97μmol, 5%. LCMS m/z 487.2 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d,J=1.4 Hz, 1H), 7.57 (br AB quartet, J_(AB)=8.2 Hz, Δν_(AB)=36.4 Hz, 4H),7.46 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H, assumed; partiallyobscured by solvent peak), 7.14-7.15 (m, 1H), 4.39-4.51 (m, 2H), 4.28(ddd, half of ABXY pattern, J=14.3, 8.0, 4.1 Hz, 1H), 4.10 (dd, J=13.9,3.1 Hz, 1H), 4.01 (ddd, J=13.5, 8.0, 4.1 Hz, 1H), 3.80 (ddd, J=13.5,7.2, 4.1 Hz, 1H), 3.34 (dd, J=14.0, 8.1 Hz, 1H), 2.30 (d, J=1.0 Hz, 3H),2.17-2.25 (m, 3H), 1.63-1.73 (m, 1H), 1.50 (s, 3H). The second-elutingpeak was Example 12, obtained as a solid. Yield: 39 mg, 80 μmol, 4%.LCMS m/z 487.2 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=1.2 Hz, 1H),7.59-7.63 (m, 2H), 7.50-7.54 (m, 2H), 7.46 (d, J=7.6 Hz, 1H), 7.28 (d,J=7 Hz, 1H, assumed; partially obscured by solvent peak), 7.13-7.15 (m,1H), 4.39-4.50 (m, 2H), 4.28 (ddd, half of ABXY pattern, J=14.2, 7.9,4.0 Hz, 1H), 4.10 (dd, J=13.9, 3.1 Hz, 1H), 4.01 (ddd, J=13.5, 7.9, 4.0Hz, 1H), 3.80 (ddd, J=13.5, 7.2, 4.1 Hz, 1H), 3.33 (dd, J=14.0, 8.1 Hz,1H), 2.29 (d, J=1.0 Hz, 3H), 2.17-2.25 (m, 3H), 1.63-1.73 (m, 1H), 1.50(s, 3H). The absolute stereochemistries of these compounds were assignedon the basis of the difference in their IC₅₀ values (see Table 1);compounds with the (2S,5R) configuration around the tetrahydrofuran ringare generally more potent than their (2R,5S) enantiomers.

Examples 13 and 147-(4-Methyl-1H-imidazol-1-yl)-2-({cis-2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (13) and7-(4-Methyl-1H-imidazol-1-yl)-2-({trans-2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (14)

Step 1. Synthesis of methyl5-[4-(trifluoromethyl)phenyl]furan-2-carboxylate (C64)

Methyl 5-bromofuran-2-carboxylate (497 mg, 2.42 mmol) and4-(trifluoromethyl)phenyl]boronic acid (472 mg, 2.48 mmol) were combinedin 1,4-dioxane (5 mL). Saturated aqueous sodium bicarbonate solution(5.0 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0)(140 mg, 0.121 mmol), and the reaction mixture was heated in a microwavereactor at 150° C. for 20 minutes. After dilution with dichloromethane(20 mL) and water (20 mL), the layers were separated and the aqueouslayer was extracted with dichloromethane (10 mL). The combined organiclayers were dried over magnesium sulfate, filtered, and concentrated invacuo. Purification via silica gel chromatography (Gradient: 0% to 50%ethyl acetate in heptane) afforded the product as a pale off-whitesolid. Yield: 298 mg, 1.10 mmol, 45%. LCMS m/z 271.0 [M+H⁺]. ¹H NMR (500MHz, CDCl₃) δ 7.90 (br d, J=8.3 Hz, 2H), 7.68 (br d, J=8.4 Hz, 2H), 7.28(d, J=3.7 Hz, 1H), 6.86 (d, J=3.7 Hz, 1H), 3.94 (s, 3H).

Step 2. Synthesis of methyl5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-carboxylate (C65)

Palladium hydroxide on carbon (˜50% water, 10 wt % palladium, 650 mg,0.46 mmol) was added to a solution of C64 (6.5 g, 32 mmol) in ethanol(170 mL), and the reaction mixture was hydrogenated for 3 hours at roomtemperature. The catalyst was removed via filtration; the filtrate wasconcentrated in vacuo and purified via supercritical fluidchromatography (Column: Chiralpak AD-H, 5 μm; Eluent: 9:1 carbondioxide/methanol), providing the product as an oil. Starting materialC64 was also recovered (2 g). Yield: 3.0 g, 11 mmol, 34% (44% based onrecovered starting material). ¹H NMR (400 MHz, CDCl₃) δ 7.63 (br ABquartet, J_(AB)=8.5 Hz, Δν_(AB)=15 Hz, 4H), 5.09 (dd, J=8.9, 5.8 Hz,1H), 4.65-4.69 (m, 1H), 3.81 (s, 3H), 2.33-2.45 (m, 2H), 2.18-2.27 (m,1H), 1.84-1.95 (m, 1H).

Step 3. Synthesis of methyl2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-carboxylate(C66)

A −100° C. solution of potassium bis(trimethylsilyl)amide (1 M intetrahydrofuran, 9.1 mL, 9.1 mmol) was added to a solution of C65 (1.25g, 4.56 mmol) and iodomethane (98%, 2.90 mL, 45.6 mmol) in diethyl ether(5 mL) at −100° C., and the reaction mixture was allowed to graduallywarm to room temperature. Upon reaction completion, aqueous citric acidsolution (1 M, 5 mL) was added. The aqueous layer was extracted withdiethyl ether (2×10 mL), and the combined organic layers were washedwith saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and concentrated in vacuo. Silica gel chromatography(Eluent: 4:1 heptane/ethyl acetate) provided the product. By ¹H NMR,this material appeared to be a roughly 1:1 mixture, presumed to consistof the cis and trans isomers of the product. Yield: 560 mg, 1.94 mmol,42%. ¹H NMR (400 MHz, CDCl₃) δ {7.60 (s) and [7.60 (br d, J=8 Hz) and7.45-7.49 (m)], total 4H}, [5.20 (dd, J=7.0, 7.0 Hz) and 5.14 (dd,J=9.4, 5.8 Hz), total 1H], 3.80 and 3.79 (2 s, total 3H), 2.34-2.58 (m,2H), 1.82-2.07 (m, 2H), 1.65 and 1.60 (2 s, total 3H).

Step 4. Synthesis of{2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol(C67)

Lithium aluminum hydride (2 M solution in tetrahydrofuran, 0.26 mL, 0.52mmol) was added to a solution of C66 (125 mg, 0.434 mmol) in diethylether (2 mL), and the reaction mixture was stirred at room temperaturefor 1 hour. After acidification with aqueous hydrochloric acid, themixture was extracted with ethyl acetate, and the combined organiclayers were dried over magnesium sulfate, filtered, and concentrated invacuo to afford the product as an oil, presumed to be a ˜1:1 mixture ofstereoisomers. Yield: 85 mg, 0.33 mmol, 76%. ¹H NMR (400 MHz, CDCl₃) δ7.59 (br d, J=8.2 Hz, 2H), 7.43-7.49 (m, 2H), 4.97-5.08 (m, 1H),3.51-3.63 (m, 2H), 2.32-2.44 (m, 1H), 2.08-2.19 (m, 1H), 1.76-1.95 (m,2H), 1.34 and 1.33 (2 s, total 3H).

Step 5. Synthesis of{2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methylmethanesulfonate (C68)

Compound C67 was converted to the product using the general methoddescribed for synthesis of C17 in Example 3. The product, isolated as aroughly 1:1 mixture of stereoisomers, was used without additionalpurification. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 7.60 (brd, J=8.6 Hz, 2H), 7.44-7.50 (m, 2H), 5.04-5.10 (m, 1H), [4.21 (ABquartet, J_(AB)=10.4 Hz, Δν_(AB)=17.5 Hz) and 4.19 (s), total 2H], 3.08and 3.03 (2 s, total 3H), 1.44 and 1.41 (2 s, total 3H).

Step 6. Synthesis of2-[({2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol(C69)

The product was prepared from C68 using the general method described forsynthesis of C9 in Example 1. In this case, the product was used in thenext step without HPLC purification. Yield: 295 mg, 0.973 mmol, 94%.

Step 7. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-({cis-2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (13) and7-(4-methyl-1H-imidazol-1-yl)-2-({trans-2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (14)

Compound C69 was reacted with P2 according to the method described forsynthesis of 1 in Example 1. In this case, the crude reaction mixturewas simply concentrated in vacuo and the isomers were separated via HPLC(Column: Phenomenex Luna C-18(2), 5 μm; Mobile phase A: 0.1% formic acidin water; Mobile phase B: 0.1% formic acid in methanol; Gradient: 5% to95% B). Example 13 was the first-eluting isomer, isolated as a glass.Yield: 38 mg, 71 μmol, 7%. LCMS m/z 487.3 [M+H⁺]. ¹H NMR (400 MHz,CDCl₃) δ 8.39 (s, 1H), 8.23 (br s, 1H), 7.62 (br d, J=8 Hz, 2H), 7.51(d, J=7.8 Hz, 1H), 7.43 (br d, J=8 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H),7.14-7.18 (m, 1H), 5.07 (dd, J=7.6, 7.2 Hz, 1H), 4.20-4.35 (m, 2H), 4.11(d, J=14.0 Hz, 1H), 3.97-4.05 (m, 1H), 3.78-3.86 (m, 1H), 3.50 (d,J=14.0 Hz, 1H), 2.44-2.53 (m, 1H), 2.30 (s, 3H), 2.04-2.13 (m, 1H),1.92-2.01 (m, 1H), 1.80-1.91 (m, 1H), 1.36 (s, 3H). The second-elutingisomer was Example 14, obtained as a glass. Yield: 26 mg, 49 μmol, 5%.LCMS m/z 487.3 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.23 (brs, 1H), 7.61 (br d, J=8 Hz, 2H), 7.55 (d J=7.6 Hz, 1H), 7.44 (br d, J=8Hz, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.16-7.20 (m, 1H), 5.02 (dd, J=9.4, 5.8Hz, 1H), 4.28-4.43 (m, 2H), 4.03 (ddd, half of ABXY pattern, J=13.7,7.3, 4.2 Hz, 1H), 3.94 (d, J=14.2 Hz, 1H), 3.85-3.93 (m, 1H), 3.62 (d,J=14.1 Hz, 1H), 2.35-2.44 (m, 1H), 2.32 (s, 3H), 1.85-2.10 (m, 3H), 1.38(s, 3H). The indicated stereochemistries were assigned on the basis ofNOE studies carried out on both isomers.

Examples 15 and 167-(4-Methyl-1H-imidazol-1-yl)-2-({trans-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (15) and7-(4-Methyl-1H-imidazol-1-yl)-2-({cis-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (16)

Step 1. Synthesis of 1-[4-(trifluoromethyl)phenyl]hex-5-en-1-ol (C70)

A mixture of 5-bromopent-1-ene (6.0 g, 40 mmol) and magnesium (1.44 g,59.2 mmol) in tetrahydrofuran (40 mL) was stirred at 0° C. for 30minutes. 4-(Trifluoromethyl)benzaldehyde (4.6 g, 26 mmol) was addeddrop-wise, and the reaction mixture was stirred at room temperature for4 hours, then quenched by addition of water (30 mL). After extractionwith ethyl acetate (3×15 mL), the combined organic layers were washedwith saturated aqueous sodium chloride solution (10 mL), dried oversodium sulfate, filtered, and concentrated in vacuo to afford theproduct as a yellow oil. This was used without additional purification.Yield: 2.6 g, 11 mmol, 42%. ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.64 (m, 2H),7.44-7.50 (m, 2H), 5.72-5.84 (m, 1H), 4.93-5.04 (m, 2H), 4.73-4.79 (m,1H), 2.05-2.13 (m, 2H), 1.64-1.85 (m, 2H), 1.47-1.60 (m, 1H), 1.34-1.47(m, 1H).

Step 2. Synthesis of2-(iodomethyl)-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran (C71)

To a solution of C70 (2.3 g, 9.4 mmol) in acetonitrile (25 mL) was addedN-iodosuccinimide (95%, 5.0 g, 21 mmol), and the reaction mixture wasstirred at room temperature for 18 hours. After quenching with water (15mL), the mixture was extracted with ethyl acetate (3×15 mL), and thecombined organic layers were washed with saturated aqueous sodiumchloride solution (15 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Purification via silica gel chromatography(Gradient: 1% to 10% ethyl acetate in petroleum ether) provided theproduct as a yellow oil. By ¹H NMR, this consisted of a roughly 2:1mixture of isomers. Yield: 1.8 g, 4.9 mmol, 52%. ¹H NMR (400 MHz,CDCl₃), characteristic peaks: δ [7.51 (d, J=8.5 Hz) and 7.56-7.67 (m),total 4H], [4.51 (br d, J=11 Hz) and 4.93 (br dd, J=5, 5 Hz), total 1H],[3.48-3.57 (m) and 3.78-3.86 (m), total 1H], 3.26-2.42 (m, 2H).

Step 3. Synthesis of2-[({6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)amino]ethanol(C72)

Compound C71 was converted to the product using the method described forsynthesis of C29 in Example 6. The product was obtained as a yellow oil,which by ¹H NMR was estimated to be a roughly 3:1 mixture of isomers.Yield: 1.1 g, 3.6 mmol, 73%. ¹H NMR (400 MHz, CDCl₃), characteristicpeaks: δ 7.41-7.66 (m, 4H), [4.43 (br d, J=10.5 Hz) and 4.88 (br dd,J=5, 5 Hz), total 1H].

Step 4. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-({trans-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (15) and7-(4-methyl-1H-imidazol-1-yl)-2-({cis-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,formate salt (16)

Compound C72 was reacted with P2 using the method described forsynthesis of 1 in Example 1. In this case, the separation ofstereoisomers was carried out via reversed phase HPLC (Column: BostonAnalytics, Boston Symmetrix ODS-H, 5 μm; Mobile phase A: 0.225% formicacid in water; Mobile phase B: 0.225% formic acid in acetonitrile;Gradient: 24% to 44% B). Example 16 came off the column before Example15; both were obtained as white solids. The indicated relativestereochemistry was assigned on the basis of NOE studies. Example 15:Yield, 4.7 mg, 8.8 μmol, 1.3%. LCMS m/z 487.0 [M+H⁺]. ¹H NMR (400 MHz,CD₃OD) δ 8.57 (br s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.57 (br AB quartet,J_(AB)=8 Hz, Δν_(AB)=21 Hz, 4H), 7.39-7.42 (m, 1H), 7.23 (d, J=8.0 Hz,1H), 5.01-5.06 (m, 1H), 4.30-4.36 (m, 2H), 4.17-4.27 (m, 2H), 3.83-3.88(m, 2H), 3.48-3.57 (m, 1H), 2.28 (br s, 3H), 1.70-2.0 (m, 5H), 1.56-1.66(m, 1H). Example 16: 32.8 mg, 61.6 μmol, 9%. ¹H NMR (400 MHz, CD₃OD) δ9.05 (br s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.58 (br AB quartet, J_(AB)=8.5Hz, Δν_(AB)=31 Hz, 4H), 7.58 (br s, 1H), 7.28 (d, J=7.5 Hz, 1H), 4.52(br d, J=10.5 Hz, 1H), 4.30-4.38 (m, 1H), 4.21-4.29 (m, 1H), 3.85-3.98(m, 4H), 3.62 (dd, J=13.8, 8.3 Hz, 1H), 2.36 (s, 3H), 1.97-2.05 (m, 1H),1.72-1.93 (m, 3H), 1.34-1.52 (m, 2H).

Example 177-(4-Methyl-1H-imidazol-1-yl)-2-({(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,trifluoroacetate salt (17)

Step 1. Synthesis of(3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-methyldihydrofuran-2(3H)-one(C73)

A solution of C30 (1.02 g, 2.88 mmol) in tetrahydrofuran (15 mL) wasadded drop-wise to a −78° C. solution of lithiumbis(trimethylsilyl)amide (1.0 M in heptane, 3.45 mL, 3.45 mmol) intetrahydrofuran (12 mL); after 30 minutes, iodomethane (0.215 mL, 3.45mmol) was added to the cold solution, which was then stirred at −78° C.for 30 minutes, warmed to −50° C. and stirred at that temperature for 3hours. After quenching with aqueous ammonium chloride solution (50%saturated, 20 mL), diethyl ether (20 mL) was added, and the aqueouslayer was extracted with diethyl ether (2×20 mL). The combined organiclayers were washed with saturated aqueous sodium chloride solution,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresulting oil (1.27 g) was dissolved in tetrahydrofuran (15 mL) andadded drop-wise to a −78° C. solution of lithiumbis(trimethylsilyl)amide (1.0 M in heptane, 5.0 mL, 5.0 mmol) intetrahydrofuran (10 mL). After the reaction mixture had stirred at −78°C. for 1 hour, it was allowed to warm briefly to −50° C., then cooledback to −78° C. Saturated aqueous sodium sulfate solution (10 mL) wasadded, and the mixture was allowed to slowly thaw. Water (10 mL) anddiethyl ether (20 mL) were added, and the aqueous layer was extractedwith diethyl ether (2×20 mL). The combined organic layers were washedwith saturated aqueous sodium chloride solution, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Purificationusing silica gel chromatography (0% to 50% ethyl acetate in heptane)afforded the product as a colorless oil, which subsequently solidified.The indicated stereochemistry was assigned in accordance with the workof S. F. Martin et al., J. Org. Chem. 2000, 65, 1305-1318. Yield: 558mg, 1.51 mmol, 52%. ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.70 (m, 4H),7.38-7.48 (m, 6H), 4.44-4.51 (m, 1H), 3.87 (dd, half of ABX pattern,J=11.3, 3.7 Hz, 1H), 3.74 (dd, half of ABX pattern, J=11.5, 4.3 Hz, 1H),2.71 (ddq, J=11.6, 9.1, 7.1 Hz, 1H), 2.39 (ddd, J=12.5, 9.2, 6.2 Hz,1H), 1.86 (ddd, J=12.5, 11.7, 10.0 Hz, 1H), 1.30 (d, J=7.2 Hz, 3H), 1.07(s, 9H).

Step 2. Synthesis of(3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-methyl-2-(4-(trifluoromethyl)phenyl)tetrahydrofuran-2-ol(C74)

Compound C73 was converted to the product using the method for synthesisof C25 in Example 6. The product, obtained as an orange oil, was takendirectly to the following step.

Step 3. Synthesis oftert-butyl({(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methoxy)diphenylsilane(C75)

Compound C74 (≦1.51 mmol) was converted to the product, obtained as anoil, using the method described for synthesis of C26 in Example 6.Yield: 336 mg, 0.674 mmol, 45% over 2 steps. ¹H NMR (400 MHz, CDCl₃) δ7.73-7.78 (m, 4H), 7.53 (br d, J=8.2 Hz, 2H), 7.37-7.48 (m, 8H), 5.06(d, J=7.4 Hz, 1H), 4.14-4.21 (m, 1H), 3.95 (dd, half of ABX pattern,J=10.9, 4.1 Hz, 1H), 3.86 (dd, half of ABX pattern, J=10.9, 4.7 Hz, 1H),2.59-2.71 (m, 1H), 2.17 (ddd, J=12.4, 7, 7 Hz, 1H), 1.66 (ddd, J=12.4,8.8, 7.5 Hz, 1H), 1.11 (s, 9H), 0.58 (d, J=7.0 Hz, 3H).

Step 4. Synthesis of{(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol(C76)

Deprotection of C75 was carried out using the method described forsynthesis of C27 in Example 6. The product was obtained as an oil. Theindicated stereochemistry for the aryl group was assigned on the basisof NOE experiments. Yield: 139 mg, 0.534 mmol, 81%. GCMS m/z 260 [M⁺].¹H NMR (400 MHz, CDCl₃) δ 7.60 (br d, J=8.2 Hz, 2H), 7.39-7.43 (m, 2H),5.06 (d, J=7.0 Hz, 1H), 4.14-4.21 (m, 1H), 3.90 (dd, half of ABXpattern, J=11.7, 3.3 Hz, 1H), 3.77 (dd, half of ABX pattern, J=11.7, 6.2Hz, 1H), 2.62-2.73 (m, 1H), 2.24 (ddd, J=12.5, 7.6, 7.0 Hz, 1H), 1.49(ddd, J=12.5, 8.6, 6.6 Hz, 1H), 0.60 (d, J=7.0 Hz, 3H).

Step 5. Synthesis of{(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methylmethanesulfonate (C77)

Compound C76 was converted to the product using the method described forsynthesis of C8 in Example 1; the product was obtained as an oil. Yield:176 mg, 0.520 mmol, 100%. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (br d, J=8 Hz,2H), 7.38-7.42 (m, 2H), 5.09 (d, J=7.2 Hz, 1H), 4.41-4.49 (m, 2H),4.30-4.37 (m, 1H), 3.11 (s, 3H), 2.63-2.75 (m, 1H), 2.34 (ddd, J=12.7,7.4, 7.4 Hz, 1H), 1.53 (ddd, J=12.7, 8.4, 6.6 Hz, 1H), 0.62 (d, J=7.0Hz, 3H).

Step 6. Synthesis of2-[({(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol(C78)

The product, obtained as an oil, was prepared from C77 using the methodemployed for synthesis of C29 in Example 6. Yield: 132 mg, 0.435 mmol,86%. LCMS m/z 304.4 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (br d, J=8Hz, 2H), 7.36-7.41 (m, 2H), 5.03 (d, J=7.4 Hz, 1H), 4.15-4.23 (m, 1H),3.67-3.71 (m, 2H), 2.82-3.00 (m, 4H), 2.59-2.71 (m, 1H), 2.29 (ddd,J=12.3, 7.6, 6.8 Hz, 1H), 1.38 (ddd, J=12.5, 8.6, 7.0 Hz, 1H), 0.59 (d,J=7.0 Hz, 3H).

Step 7. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,trifluoroacetate salt (17)

Conversion of C78 to the product was carried out using the methoddescribed for synthesis of 6 in Example 6. After the chromatography onsilica gel, the product was purified by reversed phase HPLC (Column:Waters Sunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid inwater (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile(v/v); Gradient: 5% to 100% B), affording the product as a solid. Yield:12 mg, 20 μmol, 4%. LCMS m/z 487.3 [M+H⁺]. ¹H NMR (600 MHz, DMSO-d₆) δ9.37 (br s, 1H), 8.05 (br d, J=7.5 Hz, 1H), 7.81 (br s, 1H), 7.70 (br d,J=7.9 Hz, 2H), 7.52 (br d, J=7.9 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 5.04(d, J=7.0 Hz, 1H), 4.21-4.31 (m, 3H), 3.83-3.96 (m, 3H), 3.70 (dd,J=13.8, 8.1 Hz, 1H), 2.62-2.68 (m, 1H), 2.31 (s, 3H), 2.28-2.36 (m, 1H),1.36-1.42 (m, 1H), 0.52 (d, J=7.0 Hz, 3H).

Example 182-({(2S,5R)-5-[3,5-Difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(18)

Step 1. Synthesis of(2S)-1-[(2-hydroxyethyl)amino]-5-(trimethylsilyl)pent-4-yn-2-ol (C79)

A mixture of (2S)-1-chloro-5-(trimethylsilyl)pent-4-yn-2-ol (80 g, 420mmol) and 2-aminoethanol (110 g, 1.8 mol) was stirred at 80° C. for 18hours. Silica gel chromatography (Gradient: 1% to 10% methanol indichloromethane) provided the product as a yellow oil. Yield: 30 g, 140mmol, 33%. ¹H NMR (400 MHz, CD₃OD) δ 3.80-3.88 (m, 1H), 3.61-3.72 (m,2H), 2.84 (dd, J=12.3, 3.3 Hz, 1H), 2.69-2.81 (m, 2H), 2.64 (dd, J=12.0,8.5 Hz, 1H), 2.45 (dd, half of ABX pattern, J=16.6, 5.5 Hz, 1H), 2.37(dd, half of ABX pattern, J=16.6, 7.0 Hz, 1H), 0.12 (s, 9H).

Step 2. Synthesis ofN-(2-hydroxyethyl)-N-[(2S)-2-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl]-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C80)

Compound C79 was converted to the product using the general methoddescribed for preparation of 1 in Example 1. In this synthesis, slightlyless than one equivalent of HATU was employed, the reaction was carriedout in acetonitrile, and the extractions were done with ethyl acetate.The crude product solution was dried over sodium sulfate in this case,and the crude product was taken directly on to the following step.

Step 3. Synthesis of2-[(2S)-2-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C81)

Diisopropyl azodicarboxylate (14 g, 69 mmol) was added drop-wise to a 0°C. mixture of crude C80 (60 mmol) and triphenylphosphine (18.9 g, 72.0mmol) in tetrahydrofuran (500 mL). After being stirred at 0° C. for 2.5hours, the reaction mixture was concentrated in vacuo; purification bysilica gel chromatography (Gradient: 1% to 6% methanol indichloromethane) afforded the product as a yellow solid. Yield: 7.0 g,18 mmol, 30% over two steps.

Step 4. Synthesis of2-[(2S)-2-hydroxypent-4-yn-1-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C82)

A mixture of C81 (6.5 g, 16 mmol) and potassium carbonate (2.25 g, 16.3mmol) in methanol (150 mL) was stirred at room temperature for 5 hours.The reaction mixture was concentrated in vacuo and purified by silicagel chromatography (Gradient: 1% to 2.5% methanol in dichloromethane) toprovide the product as a yellow solid. Yield: 2.5 g, 7.7 mmol, 48%. ¹HNMR (400 MHz, CD₃OD) δ 8.31 (d, J=1.2 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H),7.31-7.33 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 4.33-4.39 (m, 2H), 4.04-4.12(m, 1H), 3.82-3.96 (m, 3H), 3.50 (dd, J=13.7, 8.4 Hz, 1H), 2.41-2.46 (m,2H), 2.37 (t, J=2.8 Hz, 1H), 2.24 (d, J=1.0 Hz, 3H).

Step 5. Synthesis of2-{(2S)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]-2-hydroxypent-4-yn-1-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C83)

Compound C82 was reacted with5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene using the generalprocedure described for synthesis of C39 in Example 8. In this case, thereaction solvent was a 1.6:1 mixture of N,N-dimethylformamide andtriethylamine, and the catalyst employed wasdichlorobis(triphenylphosphine)palladium(II). Extraction was carried outwith ethyl acetate, and the product, obtained as a light orange solid,was purified via silica gel chromatography (Gradient: 0% to 100% [10% (2M ammonium in methanol) in ethyl acetate] in ethyl acetate). Yield: 505mg, 0.997 mmol, 65%. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=1.2 Hz, 1H),7.40 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.06-7.08 (m, 1H), 7.04(d, J=9.8 Hz, 2H), 4.41 (ddd, half of ABXY pattern, J=14.3, 7.2, 4.2 Hz,1H), 4.26-4.36 (m, 2H), 3.92-4.00 (m, 2H), 3.83 (ddd, half of ABXYpattern, J=13.5, 7.3, 4.2 Hz, 1H), 3.55 (dd, J=14.0, 8.3 Hz, 1H),2.68-2.80 (m, 2H), 2.28 (br s, 3H).

Step 6. Synthesis of2-({(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(18)

Di-μ-chlorodichlorobis(ethylene)diplatinum(II) (97%, 60 mg, 99 μmol),trifluoroacetic acid (380 μL, 5.0 mmol) and water (89 μL, 5.0 mmol) wereadded to a solution of C83 (250 mg, 0.494 mmol) in dichloromethane (5mL), and the reaction mixture was stirred at room temperature untilanalysis by thin layer chromatography indicated consumption of startingmaterial. The reaction mixture was cooled to −20° C. and treated withtrifluoroacetic acid (0.958 mL, 12.4 mmol) followed by drop-wiseaddition of triethylsilane (99%, 1.19 mL, 7.39 mmol) over 5 minutes.After slowly warming to room temperature, the reaction was allowed toproceed for 1.5 hours, whereupon dichloromethane (50 mL) was added, andthe mixture was washed with water (25 mL) and with saturated aqueoussodium chloride solution (25 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo; purification viasilica gel chromatography (Gradient: 0% to 70% [10% (2 M ammonium inmethanol) in ethyl acetate] in ethyl acetate) was followed by HPLC(Column: Phenomenex Lux Cellulose-1, 5 μm; Gradient: 70% to 100% ethanolin heptane) to provide the product as a solid. Yield: 40 mg, 79 μmol,16%. LCMS m/z 509.0 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (br s, 1H),7.49 (d, J=7.6 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.16 (br s, 1H), 6.98(d, J=10.4 Hz, 2H), 4.86-4.92 (m, 1H), 4.31-4.41 (m, 3H), 4.14 (dd,J=13.9, 2.7 Hz, 1H), 3.92-4.01 (m, 1H), 3.78-3.86 (m, 1H), 3.47 (dd,J=14.0, 8.5 Hz, 1H), 2.37-2.48 (m, 1H), 2.31 (s, 3H), 2.16-2.26 (m, 1H),1.69-1.87 (m, 2H).

Method A Preparation of 2-substituted7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionesM1 via initial reductive amination

Step 1. Synthesis of N-substituted2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine C84

A solution of the primary amine (300 μmol) in methanol (1 mL) wastreated with {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (28 μL, 150μmol) and shaken at 30° C. for 40 minutes. The reaction vial was cooledto 0° C., sodium borohydride (17 mg, 450 μmol) was added, and thereaction was shaken at 30° C. for 100 minutes. The solvent was removedin vacuo, water (1 mL) was added and the mixture was extracted withethyl acetate (3×1 mL). The combined organic layers were dried oversodium sulfate, filtered, concentrated in vacuo, and purified viapreparative thin layer chromatography.

Step 2. Synthesis of N-substituted 2-aminoethanol C85

A solution of C84 in methanol (500 μL) was treated with a solution ofacetyl chloride (188 μL) in methanol (312 μL) at 30° C. for 16 hours.The solvent was removed in vacuo.

Step 3. Synthesis of 2-substituted7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dioneM1

Compound C85 was treated with P1 (34.4 mg, 125 μmol), dichloromethane (2mL), diisopropylethylamine (217 μL, 1.25 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 97%, 122 mg, 320 μmol), then shaken at 30° C.for 16 hours. The solvent was removed in vacuo and the residue wastreated with saturated aqueous sodium bicarbonate solution (2 mL) andextracted with ethyl acetate (3×1 mL). The combined organic layers weredried over sodium sulfate, filtered, concentrated in vacuo, and purifiedvia reversed phase HPLC. Purifications were carried out using aPhenomenex Gemini C18 column (8-10 μm), with the non-aqueous mobilephase consisting of ammonium hydroxide in acetonitrile (pH 10) andemploying an appropriate gradient.

TABLE 1

Ex. #

Method of Preparation; Non- commercial Starting Materials ¹H NMR (400MHz, CDCl₃), δ (ppm); Mass spectrum, observed ion m/z (M + 1) or HPLCretention time (minutes); Mass spectrum m/z (M + 1) (unless otherwiseindicated) 19

Example 1¹ 2.20 minutes²; 426.2 20

Example 1³ characteristic peaks: 2.33 (br s, 3H), 3.65 (br dd, J = 6, 6Hz, 2H), 4.31-4.43 (m, 2H), 4.93-4.98 (m, 1H), 5.17-5.27 (m, 1H), 7.05(br dd, J = 8, 2 Hz, 1H), 7.08-7.11 (m, 1H), 7.18-7.23 (m, 2H), 7.30 (d,J = 7.8 Hz, 1H), 7.40 (br dd, J = 8, 8 Hz, 1H), 7.56 (d, J = 7.8 Hz,1H), 8.43 (br s, 1H); 473.3 21

Example 1⁴ 1.37-1.48 (m, 1H), 1.71-1.89 (m, 3H), 1.97-2.07 (m, 1H),2.12-2.22 (m, 1H), 2.29 (s, 3H), 2.50-2.61 (m, 1H), 3.43 (dd, J = 13.7,6.4 Hz, 1H), 3.65 (ddd, J = 13.3, 6.6, 4.1 Hz, 1H), 3.80 (ddd, J = 13.3,8.4, 3.9 Hz, 1H), 4.00 (dd, J = 13.7, 9.6 Hz, 1H), 4.21 (ddd, J = 14.2,8.5, 4.1 Hz, 1H), 4.44 (ddd, J = 14.2, 6.5, 4.0 Hz, 1H), 4.60-4.65 (m,1H), 6.93-6.98 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 7.11 (br s, 1H), 7.15(br d, J = 7.7 Hz, 1H), 7.32 (br dd, J = 8.1, 7.7 Hz, 1H), 7.34 (d, J =7.7 Hz, 1H), 8.21 (br s, 1H); 487.3 22

Example 1⁵ 2.55 minutes²; 459.2 23

Example 1; P5 1.03-1.49 (m, 4H), 1.75-2.00 (m, 5H), 2.27 (d, J = 0.8 Hz,3H), 2.47-2.56 (m, 1H), 3.44-3.48 (m, 2H), 3.68 (dd, J = 5.8, 5.7 Hz,2H), 4.28-4.40 (m, 2H), 7.09-7.13 (m, 3H), 7.22-7.26 (m, 3H), 7.43 (d, J= 7.6 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H); 451.1 24

Method A⁶ 2.72 minutes⁷; 425 25

Method A⁹ 2.85 minutes⁷; 439 26

Example 1¹⁰ 2.65 minutes²; 491.1 27

Example 1; P4 2.44 minutes²; 459.2 28

Example 1¹² 2.26 minutes²; 453.0, 455.0 29

Example 1; P5¹³ 1.04-1.28 (m, 2H), 1.31-1.50 (m, 2H), 1.76-2.01 (m, 5H),2.29 (br s, 3H), 2.48-2.58 (m, 1H), 3.45-3.49 (m, 2H), 3.67-3.72 (m,2H), 4.29-4.42 (m, 2H), 7.11-7.15 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H),7.25 (d, J = 8.4 Hz, 2H), 7.24-7.28 (m, 1H, assumed; obscured by solventpeak), 7.44 (d, J = 7.4 Hz, 1H), 8.22 (br s, 1H); 451 30

Example 4 2.49 minutes²; 506.3, 508.3 31

Example 4 2.60 minutes²; 524.3, 526.3 32

Example 4 2.46 minutes²; 506.3, 508.3 33

Example 3 2.58 minutes²; 459.3 34

Example 3 2.60 minutes²; 493.0, 493.5 35

Example 3 2.48 minutes²; 449.0 36

Example 3¹⁴ 2.61 minutes²; 457.0, 459.0 37

Example 3¹⁵ 2.85 minutes²; 467.1, 469.0 38

Example 3 2.57 minutes²; 441.1 39

Example 3¹⁶ 2.62 minutes²; 459.1 40

Example 3¹⁷ 2.69 minutes²; 451.2 41

Example 3 2.65 minutes²; 493.0, 495.0 42

Example 1¹⁸ 2.63 minutes²; 473.1, 475.1 43

Example 7 8.29 (d, J = 1.2 Hz, 1H), 7.62 (br d, J = 8.2 Hz, 2H), 7.47(d, J = 7.8 Hz, 1H), 7.42-7.46 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H),7.14-7.16 (m, 1H), 4.92-4.97 (m, 1H), 4.28-4.43 (m, 3H), 4.19 (dd, J =14.0, 3.0 Hz, 1H), 4.00 (ddd, half of ABXY pattern, J = 13.5, 7.6, 4.3Hz, 1H), 3.82 (ddd, half of ABXY pattern, J = 13.5, 7.2, 4.1 Hz, 1H),3.44 (dd, J = 14.0, 8.2 Hz, 1H), 2.37-2.46 (m, 1H), 2.31 (d, J = 1.0 Hz,3H), 2.16-2.26 (m, 1H), 1.73-1.89 (m, 2H); 473.2 44

Example 7^(19,20) 8.51 (br s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.33 (br d,half of AB quartet, J = 8.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.24-7.28(m, 2H, assumed; partially obscured by solvent peak), 7.17-7.20 (m, 1H),4.86 (dd, J = 7.4, 6.8 Hz, 1H), 4.26-4.42 (m, 3H), 4.17 (dd, J = 14.0,2.9 Hz, 1H), 3.98 (ddd, half of ABXY pattern, J = 13.5, 7.5, 4.2 Hz,1H), 3.81 (ddd, half of ABXY pattern, J = 13.5, 7.3, 4.2 Hz, 1H), 3.42(dd, J = 14.0, 8.2 Hz, 1H), 2.35 (d, J = 0.8 Hz, 3H), 2.31-2.40 (m, 1H),2.14-2.23 (m, 1H), 1.72-1.87 (m, 2H); 439.1 45

Example 7^(21,22) 8.22 (d, J = 1.2 Hz, 1H), 7.75 (br d, J = 8.8 Hz, 2H),7.45 (d, J = 7.6 Hz, 1H), 7.42 (br d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.8Hz, 1H), 7.13-7.15 (m, 1H), 4.91-4.96 (m, 1H), 4.29-4.43 (m, 3H), 4.18(dd, J = 14.1, 2.9 Hz, 1H), 3.99 (ddd, half of ABXY pattern, J = 13.5,7.3, 4.5 Hz, 1H), 3.82 (ddd, half of ABXY pattern, J = 13.4, 7.1, 4.4Hz, 1H), 3.45 (dd, J = 14.0, 8.5 Hz, 1H), 2.38-2.47 (m, 1H), 2.29 (br s,3H), 2.16-2.25 (m, 1H), 1.72-1.88 (m, 2H); 531.2 46

Example 6^(23,24) 8.22 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H),7.33-7.38 (m, 2H), 7.27-7.30 (m, 1H, assumed; partially obscured bysolvent peak), 7.19-7.24 (m, 2H), 7.13-7.15 (m, 1H), 4.87-4.92 (m, 1H),4.27-4.43 (m, 3H), 4.18 (dd, J = 13.9, 2.9 Hz, 1H), 3.94-4.02 (m, 1H),3.77-3.84 (m, 1H), 3.43 (dd, J = 13.9, 8.2 Hz, 1H), 2.34-2.42 (m, 1H),2.28-2.31 (m, 3H), 2.15-2.24 (m, 1H), 1.73-1.89 (m, 2H); 489.2 47

Example 7 9.45 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.59 (dd,J = 7.6, 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.32-7.36 (m, 1H),7.16-7.21 (m, 2H), 4.90-4.96 (m, 1H), 4.32-4.42 (m, 3H), 4.15-4.21 (m,1H), 3.98-4.06 (m, 1H), 3.82-3.90 (m, 1H), 3.47 (dd, J = 14.1, 8.6 Hz,1H), 2.55 (d, J = 1.0 Hz, 3H), 2.38-2.48 (m, 1H), 2.18-2.27 (m, 1H),1.71-1.89 (m, 2H); 491.0 48

Example 7 8.22 (br s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.8Hz, 1H), 7.21 (br d, J = 8.2 Hz, 2H), 7.12-7.15 (m, 1H), 7.06 (br d, J =8.0 Hz, 2H), 4.82-4.88 (m, 1H), 4.21-4.41 (m, 3H), 4.16 (dd, J = 14.0,2.6 Hz, 1H), 3.93-4.02 (m, 1H), 3.76-3.84 (m, 1H), 3.41 (dd, J = 14, 8Hz, 1H), 2.29 (br s, 3H), 2.26-2.37 (m, 1H), 2.12-2.22 (m, 1H),1.73-1.94 (m, 3H), 0.94-1.00 (m, 2H), 0.67-0.72 (m, 2H); 7.45 minutes²⁵49

Example 7²⁶ 8.21 (br s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.31 (br d, J =8.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.11-7.15 (m, 1H), 6.94 (dd, J =8.1, 1.9 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 5.05-5.10 (m, 1H), 4.23-4.42(m, 3H), 4.18 (dd, J = 13.9, 2.9 Hz, 1H), 4.00 (ddd, J = 13.5, 7.5, 4.4Hz, 1H), 3.81 (s, 3H), 3.78-3.87 (m, 1H), 3.40-3.51 (m, 1H), 2.34-2.45(m, 1H), 2.28 (br s, 3H), 2.08-2.18 (m, 1H), 1.61-1.73 (m, 2H); 469.2 50

Example 8 8.23 (br s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.33-7.41 (m, 2H),7.29 (d, J = 7.6 Hz, 1H), 7.11-7.14 (m, 1H), 5.12-5.19 (m, 1H),4.83-4.93 (m, 1H), 4.35-4.44 (m, 1H), 4.26-4.35 (m, 1H), 4.05-4.13 (m,1H), 3.71-3.79 (m, 1H), 3.62-3.71 (m, 1H), 2.45-2.57 (m, 1H), 2.28 (s,3H), 2.15-2.25 (m, 1H), 1.84-1.95 (m, 1H), 1.71-1.82 (m, 1H), 1.30 (d, J= 6.9 Hz, 3H); 523.3 51

Example 8^(27,28,29); P3 8.25 (br s, 1H), 7.55 (br dd, J = 8, 7 Hz, 1H),7.47 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.12-7.21 (m, 3H),4.81-4.93 (m, 2H), 4.44 (ddd, J = 14.1, 6.9, 4.0 Hz, 1H), 4.24 (ddd, J =14.1, 8.1, 4.0 Hz, 1H), 4.08-4.15 (m, 1H), 3.76 (ddd, half of ABXYpattern, J = 13.4, 8.2, 3.9 Hz, 1H), 3.67 (ddd, half of ABXY pattern, J= 13.4, 6.9, 4.1 Hz, 1H), 2.38-2.46 (m, 1H), 2.30 (d, J = 0.9 Hz, 3H),2.16-2.25 (m, 1H), 1.77-1.91 (m, 2H), 1.32 (d, J = 6.9 Hz, 3H); 505.0 52

Example 9²⁹ 8.42 (br s, 1H), 7.53 (br d, J = 7.9 Hz, 1H), 7.51 (d, J =7.7 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.23 (br d, J = 8 Hz, 1H),7.14-7.16 (m, 1H), 7.02 (br s, 1H), 5.12-5.17 (m, 1H), 4.85-4.93 (m,1H), 4.40 (ddd, half of ABXY pattern, J = 14, 7, 4 Hz, 1H), 4.31 (ddd,half of ABXY pattern, J = 14, 7.5, 4 Hz, 1H), 4.03-4.10 (m, 1H), 3.86(s, 3H), 3.82 (ddd, J = 13, 7.5, 4 Hz, 1H), 3.69 (ddd, J = 13, 7, 4 Hz,1H), 2.43-2.53 (m, 1H), 2.34 (d, J = 0.8 Hz, 3H), 2.10-2.19 (m, 1H),1.67-1.79 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H); 517.3 53

Example 9^(30,29) 8.31 (br s, 1H), 7.71 (br d, J = 8 Hz, 1H), 7.52-7.59(m, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.13-7.15(m, 1H), 5.20-5.25 (m, 1H), 4.94 (dq, J = 9.0, 6.9 Hz, 1H), 4.44 (ddd,half of ABXY pattern, J = 14.2, 7.2, 4.0 Hz, 1H), 4.31 (ddd, half ofABXY pattern, J = 14.1, 7.7, 4.1 Hz, 1H), 4.06-4.14 (m, 1H), 3.77 (ddd,half of ABXY pattern, J = 13.3, 7.7, 4.0 Hz, 1H), 3.69 (ddd, half ofABXY pattern, J = 13.4, 7.2, 4.1 Hz, 1H), 2.56-2.65 (m, 1H), 2.31 (d, J= 1.0 Hz, 3H), 2.15-2.24 (m, 1H), 1.69-1.87 (m, 2H), 1.32 (d, J = 6.9Hz, 3H); 521.2 54

Example 10^(31,32) 8.23 (br s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.34 (d, J= 7.4 Hz, 1H), 7.27-7.33 (m, 1H, assumed; partially obscured by solventpeak), 7.13-7.15 (m, 1H), 7.07 (dd, J = 9.2, 6.0 Hz, 1H), 5.01-5.06 (m,1H), 4.82-4.91 (m, 1H), 4.49 (ddd, J = 14.0, 6.2, 4.3 Hz, 1H), 4.23(ddd, J = 14, 8, 4 Hz, 1H), 4.03-4.10 (m, 1H), 3.63-3.79 (m, 2H),2.40-2.49 (m, 1H), 2.29 (s, 3H), 2.15-2.24 (m, 1H), 1.75-1.88 (m, 2H),1.32 (d, J = 7.0 Hz, 3H); 489.2 55

Example 10^(31,32) 8.26 (br s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.33 (d J= 7.6 Hz, 1H), 7.12-7.15 (m, 1H), 6.96 (br d, J = 7.8 Hz, 2H), 4.78-4.88(m, 2H), 4.48 (ddd, J = 14.2, 6.4, 4.0 Hz, 1H), 4.20 (ddd, J = 14.1,8.4, 4.1 Hz, 1H), 4.05-4.12 (m, 1H), 3.62-3.77 (m, 2H), 2.33-2.42 (m,1H), 2.30 (s, 3H), 2.15-2.26 (m, 1H), 1.76-1.88 (m, 2H), 1.31 (d, J =6.8 Hz, 3H); 489.2 56

Example 6^(33,34) 8.24 (br s, 1H), 7.46-7.60 (m, 4H), 7.46 (d, J = 7.6Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.13-7.16 (m, 1H), 4.91-4.97 (m, 1H),4.26-4.42 (m, 3H), 4.17 (dd, J = 14.0, 2.9 Hz, 1H), 3.98 (ddd, J = 13.5,7.6, 4.3 Hz, 1H), 3.82 (ddd, J = 13.5, 7.3, 4.2 Hz, 1H), 3.46 (dd, J =14.0, 8.1 Hz, 1H), 2.37-2.46 (m, 1H), 2.29 (d, J = 0.8 Hz, 3H),2.17-2.25 (m, 1H), 1.74-1.90 (m, 2H); 473.2 57

Example 8^(32,29,35) 8.35 (br s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.36 (d,J = 7.4 Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 7.12-7.18 (m, 1H), 6.80 (d, J= 5.8 Hz, 1H), 5.00-5.06 (m, 1H), 4.81-4.90 (m, 1H), 4.50 (ddd, J =14.1, 6.6, 3.9 Hz, 1H), 4.21 (ddd, J = 14.1, 8.6, 3.9 Hz, 1H), 3.99-4.07(m, 1H), 3.78 (s, 3H), 3.73-3.82 (m, 1H), 3.68 (ddd, half of ABXYpattern, J = 13.3, 6.6, 3.9 Hz, 1H), 2.38-2.47 (m, 1H), 2.32 (br s, 3H),2.12-2.21 (m, 1H), 1.63-1.80 (m, 2H), 1.31 (d, J = 7.0 Hz, 3H); 501.2 58

Example 8^(32,29,36) 8.34 (br s, 1H), 7.47-7.53 (m, 2H), 7.31 (d, J =7.8 Hz, 1H), 7.25-7.29 (m, 1H, assumed; partially obscured by solventpeak), 7.20-7.23 (m, 1H), 7.13-7.16 (m, 1H), 5.09 (br dd, J = 7.4, 7.0Hz, 1H), 4.83-4.92 (m, 1H), 4.40 (ddd, half of ABXY pattern, J = 14.1,7.0, 3.9 Hz, 1H), 4.29 (ddd, half of ABXY pattern, J = 14.1, 7.8, 4.3Hz, 1H), 4.02-4.10 (m, 1H), 3.76 (ddd, half of ABXY pattern, J = 13.5,7.4, 3.7 Hz, 1H), 3.67 (ddd, half of ABXY pattern, J = 13.5, 7.2, 3.9Hz, 1H), 2.39-2.49 (m, 1H), 2.32 (s, 3H), 2.15-2.26 (m, 1H), 1.72-1.83(m, 2H), 1.31 (d, J = 7.0 Hz, 3H); 537.2 59

Example 13³⁷ 9.49 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.76(br s, 1H), 7.63 (s, 4H), 7.33 (br d, J = 7.8 Hz, 1H), 5.01 (br dd, J =7, 7 Hz, 1H), 4.30-4.47 (m, 3H), 3.89-4.04 (m, 3H), 3.75 (dd, J = 13.9,8.4 Hz, 1H), 2.40-2.50 (m, 1H), 2.44 (s, 3H), 2.18-2.28 (m, 1H),1.78-1.90 (m, 2H); 523.3 60

Example 7^(38,39) characteristic peaks: 8.23 (d, J = 1.2 Hz, 1H), 7.50(br d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.38 (br d, J = 8.3Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.12-7.15 (m, 1H), 4.88-4.94 (m, 1H),4.25-4.42 (m, 3H), 4.18 (dd, J = 13.9, 2.9 Hz, 1H), 3.99 (ddd, J = 13.5,7.7, 4.2 Hz, 1H), 3.81 (ddd, J = 13.5, 7.2, 4.2 Hz, 1H), 3.43 (dd, J =14.0, 8.1 Hz, 1H), 2.34-2.45 (m, 1H), 2.29 (s, 3H), 2.14-2.25 (m, 1H),1.93 (t, J = 18.2 Hz, 3H); 469.3 61

Example 9^(40,41,29) ¹H NMR (600 MHz, DMSO-d₆), d 8.24 (br s, 1H), 7.80(d, J = 7.4 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.38-7.40 (m, 1H), 7.36(dd, J = 8.8, 2.6 Hz, 1H), 7.19 (t, J = 73.7 Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 5.00 (dd, J = 7.4, 7.0 Hz, 1H),4.67-4.73 (m, 1H), 4.34 (ddd, J = 14.0, 6.1, 4.0 Hz, 1H), 4.06-4.14 (m,2H), 3.77 (ddd, J = 13.6, 6.1, 4.0 Hz, 1H), 3.64 (ddd, J = 13.6, 8.8,3.5 Hz, 1H), 2.33-2.40 (m, 1H), 2.15 (s, 3H), 2.10-2.17 (m, 1H),1.73-1.79 (m, 1H), 1.62-1.70 (m, 1H), 1.23 (d, J = 7.0 Hz, 3H); 519.0,521.0 62

Example 18⁴² 8.26 (br s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8Hz, 1H), 7.15 (br s, 1H), 6.96 (d, J = 7.4 Hz, 2H), 4.82-4.87 (m, 1H),4.29-4.40 (m, 3H), 4.15 (dd, J = 14.0, 2.7 Hz, 1H), 3.93-4.01 (m, 1H),3.77-3.85 (m, 1H), 3.44 (dd, J = 13.8, 8.4 Hz, 1H), 2.34-2.43 (m, 1H),2.30 (s, 3H), 2.14-2.24 (m, 1H), 1.70-1.85 (m, 2H); 475.2 63

Example 7⁴³ ¹H NMR (600 MHz, DMSO-d₆), δ 9.29 (br s, 1H), 8.02 (d, J =7.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.77 (br s, 1H), 7.66-7.75 (m,2H), 7.50 (dd, J = 7.9, 7.5 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.11 (brdd, J = 7, 7 Hz, 1H), 4.24-4.32 (m, 3H), 3.82-3.90 (m, 3H), 3.78 (dd,half of ABX pattern, J = 13.6, 7.9 Hz, 1H), 2.30 (s, 3H), 2.3-2.35 (m,1H), 2.10-2.17 (m, 1H), 1.75-1.82 (m, 1H), 1.63-1.71 (m, 1H); 473.2 64

Example 17⁴⁴ 2.62 minutes²; 487.3 65

Example 18 ¹H NMR (600 MHz, DMSO-d₆), δ 9.21 (br s, 1H), 8.00 (d, J =7.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.79 (dd, J = 8.3, 2.2 Hz, 1H),7.73-7.76 (m, 2H), 7.19 (d, J = 7.9 Hz, 1H), 5.06-5.11 (m, 1H),4.25-4.32 (m, 3H), 3.83-3.88 (m, 3H), 3.78 (dd, half of ABX pattern, J =14.0, 7.9 Hz, 1H), 2.30 (s, 3H), 2.3-2.36 (m, 1H), 2.11-2.18 (m, 1H),1.75-1.82 (m, 1H), 1.64-1.71 (m, 1H); 507.2, 509.2 66

Example 8 2.67 minutes²; 523.2 67

Example 9 8.36 (br s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.6Hz, 1H), 7.21-7.24 (m, 1H), 7.13-7.16 (m, 1H), 7.06 (br dd, J = 9.5, 1.5Hz, 1H), 4.77-4.88 (m, 2H), 4.49 (ddd, J = 14.2, 6.4, 4.0 Hz, 1H), 4.20(ddd, J = 14.2, 8.5, 4.2 Hz, 1H), 4.05-4.12 (m, 1H), 3.62-3.78 (m, 2H),2.33 (br s, 3H), 2.3-2.42 (m, 1H), 2.16-2.26 (m, 1H), 1.77-1.90 (m, 2H),1.31 (d, J = 7.0 Hz, 3H); 505.3 68

Example 9³² 8.33 (br s, 1H), 7.73 (dd, J = 8.8, 5.7 Hz, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.22-7.32 (m, 3H, assumed; partially obscured by solventpeak), 7.12-7.15 (m, 1H), 5.14-5.20 (m, 1H), 4.88-4.97 (m, 1H), 4.43(ddd, J = 14.0, 7.0, 3.9 Hz, 1H), 4.26 (ddd, J = 14.1, 8.1, 4.0 Hz, 1H),4.02-4.09 (m, 1H), 3.75 (ddd, half of ABXY pattern, J = 13.4, 7.9, 3.9Hz, 1H), 3.66 (ddd, half of ABXY pattern, J = 13.3, 7.0, 4.0 Hz, 1H),2.37-2.46 (m, 1H), 2.32 (d, J = 1 Hz, 3H), 2.17-2.27 (m, 1H), 1.70-1.89(m, 2H), 1.32 (d, J = 6.8 Hz, 3H); 505.3 69

Example 9⁴⁵ 8.28 (br s, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.61 (d, J = 10.2Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.12-7.15(m, 1H), 5.10-5.16 (m, 1H), 4.94 (dq, J = 9.0, 7.0 Hz, 1H), 4.52-4.60(m, 1H), 4.12-4.20 (m, 1H), 4.02-4.09 (m, 1H), 3.63-3.75 (m, 2H),2.38-2.48 (m, 1H), 2.31 (s, 3H), 2.20-2.3 (m, 1H), 1.82-1.91 (m, 1H),1.70-1.81 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H); 539.3 70

Example 9⁴⁵ 8.27 (br s, 1H), 7.54-7.62 (m, 2H), 7.47 (d, J = 7.8 Hz,1H), 7.30 (d, J = 7.8 Hz, 1H), 7.12-7.15 (m, 1H), 5.22-5.28 (m, 1H),4.90-4.99 (m, 1H), 4.44 (ddd, J = 14, 7, 4 Hz, 1H), 4.29 (ddd, J = 14,8, 4 Hz, 1H), 4.02-4.09 (m, 1H), 3.63-3.77 (m, 2H), 2.45-2.55 (m, 1H),2.31 (s, 3H), 2.13-2.21 (m, 1H), 1.69-1.86 (m, 2H), 1.30 (d, J = 7.0 Hz,3H); 539.3 71

Example 9 ¹H NMR (600 MHz, DMSO-d₆), δ 8.24 (d, J = 1.1 Hz, 1H), 7.78(d, J = 7.9 Hz, 1H), 7.53-7.55 (m, 1H), 7.38-7.40 (m, 1H), 7.09-7.11 (m,1H), 7.08 (d, J = 7.7 Hz, 1H), 5.14-5.18 (m, 1H), 4.56-4.62 (m, 1H),4.16-4.24 (m, 2H), 4.10-4.15 (m, 1H), 3.65-3.75 (m, 2H), 2.37-2.43 (m,1H), 2.15 (d, J = 1 Hz, 3H), 2.07-2.14 (m, 1H), 1.84-1.91 (m, 1H),1.75-1.82 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H); 493.4

1. 3,4-Difluoro-N-hydroxybenzenecarboximidoyl chloride (M. R. Barbachynet al., J. Med. Chem. 2003, 46, 284-302) was subjected to acycloaddition with ethylene, and the product was acylated according tothe method of A. Corsaro et al., J. Heterocyclic Chem. 1989, 26, 1691-9,to afford methyl3-(3,4-difluorophenyl)-4,5-dihydro-1,2-oxazole-4-carboxylate. Afterammonolysis, the resulting primary amide was converted to thetert-butoxycarbonyl-protected amine via a Hofmann rearrangement.Deprotection and resolution with(−)-anicyphos[(4S)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide]yielded (4R)-3-(3,4-difluorophenyl)-4,5-dihydro-1,2-oxazol-4-amine. Thiswas converted to the requisite 2-aminoethanol using the generalprocedure described in Method A.

2. HPLC conditions. Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm;Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phaseB: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95%B over 4.0 minutes, linear; Flow rate: 2 mL/minute.

3. The reaction of tert-butyl [cis-3-hydroxycyclopentyl]carbamate (seeM. Pineschi et al., Org. Lett. 2005, 7, 3605-3607) and3-(trifluoromethyl)phenol under Mitsunobu conditions provided tert-butyl{trans-3-[3-(trifluoromethyl)phenoxy]cyclopentyl}carbamate. Deprotectionusing acidic conditions affordedtrans-3-[3-(trifluoromethyl)phenoxy]cyclopentanamine. This was convertedto the requisite 2-aminoethanol using the general procedure described inMethod A.

4. tert-Butyl[(2-hydroxycyclopentyl)methyl]carbamate was subjected toMitsunobu reaction and deprotection as described in footnote 3 to afford1-{2-[3-(trifluoromethyl)phenoxy]cyclopentyl}methanamine. This wasconverted to the requisite 2-aminoethanol using the general methoddescribed in Method A. Supercritical fluid chromatography was carriedout on the final product (Column: Chiralpak AD-H; Eluant: 7:3 carbondioxide/propanol) and the second-eluting enantiomer was collected. Theabsolute and relative configuration of this compound were notdetermined.

5. tert-Butyl(trans-3-hydroxycyclobutyl)carbamate (P. Liu, PCT Int.Appl. 2007, WO 2007062332 A2) was treated with carbon tetrabromide andtriphenylphosphine to producetert-butyl(cis-3-bromocyclobutyl)carbamate, which was subjected toreaction with 2-(trifluoromethyl)phenol, then deprotected with acid toyield trans-3-[2-(trifluoromethyl)phenoxy]cyclobutanamine. This wasconverted to the requisite 2-aminoethanol using the general methoddescribed in Method A.

6. The requisite amine may be prepared according to T. A. Shepherd etal., J. Med. Chem. 2002, 45, 2101-2111.

7. HPLC conditions. Column: Waters XBridge C18, 2.1×50 mm, 5 μm; Mobilephase A: 0.0375% trifluoroacetic acid in water (v/v); Mobile phase B:0.01875% trifluoroacetic acid in acetonitrile (v/v); Gradient: 1% to 5%B over 0.6 minutes, then 5% to 100% B over 3.4 minutes; Flow rate: 0.8mL/minute.

8. Cyclobutanecarbonitrile was alkylated with1-(bromomethyl)-4-fluorobenzene, and the product was reduced withlithium aluminum hydride to generate1-[1-(4-fluorobenzyl)cyclobutyl]methanamine.

9. Reaction of the Grignard reagent prepared from1-(bromomethyl)-3,5-difluorobenzene with 6-oxabicyclo[3.1.0]hexane gavetrans-2-(3,5-difluorobenzyl)cyclopentanol. Conversion to the mesylate,followed by displacement with sodium azide and reduction withtriphenylphosphine afforded cis-2-(3,5-difluorobenzyl)cyclopentanamine.

10. tert-Butyl[trans-3-(hydroxymethyl)cyclobutyl]carbamate and4-fluoro-2-(trifluoromethyl)phenol were used in a preparation similar tofootnote 3.

11. The commercially available amine was converted to the requisite2-aminoethanol using the general method described in Method A.

12. 2-Chlorocyclohexanone was reacted with 4-chlorophenol, followed byreductive amination with 2-aminoethanol to provide the requisite2-aminoethanol derivative.

13. Supercritical fluid chromatography was carried out on the finalproduct (Column: Chiralpak OJ-H; Eluant: 7:3 carbon dioxide/methanol)and the first eluting enantiomer was collected. NOE studies indicatedcis stereochemistry. The indicated absolute stereochemistry wasarbitrarily assigned.

14. Directed metallation of 2-chloro-1-fluoro-4-methoxybenzene withn-butyllithium and tetramethylethylenediamine allowed regiospecificintroduction of a methyl group. Subsequent methyl ether cleavage withboron tribromide afforded 3-chloro-4-fluoro-2-methylphenol.

15. 3-(Propan-2-yl)phenol was chlorinated using oxone and potassiumchloride to give the requisite phenol.

16. The requisite naphthalenol was prepared as described by J. T. Repineet al., Tetrahedron Lett. 2007, 48, 5539-5541.

17. Methyl 2-fluoro-6-hydroxybenzoate was treated with methylmagnesiumbromide to afford the tertiary alcohol, which was hydrogenated overpalladium on carbon to give the requisite phenol.

18. 5-(3,4-Dichlorophenyl)dihydrofuran-2(3H)-one (see G. J. Quallich etal., J. Org. Chem. 1990, 55, 4971-4973) was reduced withdiisobutylaluminum hydride, treated with acetic anhydride, and convertedto 5-(3,4-dichlorophenyl)tetrahydrofuran-2-carbonitrile by treatmentwith trimethylsilyl cyanide and boron trifluoride diethyl etherate.Reduction with diisobutylaluminum hydride afforded1-[5-(3,4-dichlorophenyl)tetrahydrofuran-2-yl]methanamine, which wasconverted to the requisite 2-aminoethanol using the general approachdescribed in Method A.

19. The requisite [cis-5-(4-chlorophenyl)tetrahydrofuran-2-yl]methanolwas prepared by hydrogenation of 5-(4-chlorophenyl)furan-2-carbaldehydein the presence of ruthenium(IV) oxide hydrate.

20. Example 46 was isolated from the racemic mixture via supercriticalfluid chromatography (Column: Chiralcel OJ-H, 5 μm; Eluent: 4:1 carbondioxide/methanol containing 0.2% isopropylamine), and was the second ofthe enantiomers that eluted from the column. The first-eluting materialwas the enantiomer of Example 46, and exhibited an IC₅₀ of 511 nM. Theabsolute stereochemistry of Example 46 was assigned on the basis of itslower IC₅₀ (see Table 1), in analogy to the other compounds describedherein.

21. The requisite{cis-5-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]tetrahydrofuran-2-yl}methanolwas prepared via Suzuki reaction of (5-formylfuran-2-yl)boronic acidwith 1-bromo-4-(pentafluoro-λ⁶-sulfanyl)benzene, followed byhydrogenation in the presence of ruthenium(IV) oxide hydrate.

22. Example 47 was isolated from the racemic mixture via supercriticalfluid chromatography (Column: Chiralcel OJ-H, 5 μm; Eluent: 65:35 carbondioxide/propanol containing 0.2% isopropylamine), and was the second ofthe enantiomers that eluted from the column. The first-eluting materialwas the enantiomer of Example 47, and exhibited an IC₅₀ of 329 nM. Theabsolute stereochemistry of Example 47 was assigned on the basis of itslower IC₅₀ (see Table 1), in analogy to the other compounds describedherein.

23. {cis-5-[4-(Trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol wasprepared from 5-bromofuran-2-carbaldehyde and[4-(trifluoromethoxy)phenyl]boronic acid using a method analogous tothat described in footnote 21.

24. Example 48 was isolated from the racemic mixture via supercriticalfluid chromatography (Column: Chiralcel OJ-H, 5 μm; Eluent: 3:1 carbondioxide/methanol containing 0.2% isopropylamine), and was the second ofthe enantiomers that eluted from the column. The first-eluting materialwas the enantiomer of Example 48, and exhibited an IC₅₀ of 1230 nM. Theabsolute stereochemistry of Example 48 was assigned on the basis of itslower IC₅₀ (see Table 1), in analogy to the other compounds describedherein.

25.tert-Butyl{[(2S,5R)-5-(4-chloro-2-methoxyphenyl)tetrahydrofuran-2-yl]methoxy}diphenylsilanewas prepared from(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-5-(4-chloro-2-methoxyphenyl)pent-4-yn-2-olusing the general method of T. X. M. Nguyen et al., Letters in OrganicChemistry 2009, 6, 630-636. This alkyne was prepared via reaction oftert-butyl[(2S)-oxiran-2-ylmethoxy]diphenylsilane with4-chloro-1-ethynyl-2-methoxybenzene, using n-butyllithium and borontrifluoride diethyl etherate.

26. In this case, reaction withdi-μ-chlorodichlorobis(ethylene)diplatinum(II) yielded(4S,5S)-5-(dibenzylamino)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxyhexan-1-onerather than the corresponding 2,3-dihydrofuran. Reaction withp-toluenesulfonic acid and trimethyl orthoformate, followed bysubjection to triethylsilane and boron trifluoride diethyl etherate,afforded(1S)—N,N-dibenzyl-1-{(2S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-2,3-dihydrofuran-2-yl}ethanamine.

27. The final ring closure was carried out via a Mitsunobu reactionusing diisopropyl azodicarboxylate.

28. The Sonogashira product in this case was converted to the nextintermediate using aqueous platinum(II) chloride.

29. The final ring closure was effected with cesium carbonate inN,N-dimethylformamide rather than lithium bis(trimethylsilyl)amide.

30. The requisite (1S)-1-[(2S,5R)-5-aryltetrahydrofuran-2-yl]ethanaminewas prepared from C48 according to Example 9, except that theSonogashira product in this case was converted to intermediatetert-butyl{(1S)-1-[(2S)-5-hydroxy-5-aryltetrahydrofuran-2-yl]ethyl}carbamate ortert-butyl{(1S)-1-[(2S)-5-methoxy-5-aryltetrahydrofuran-2-yl]ethyl}carbamateusing, respectively, aqueous platinum(II) chloride or platinum(II)chloride and trimethyl orthoformate.

31.2-[({cis-5-[3-(Trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanolwas prepared via reaction ofcis-2-(bromomethyl)-5-[3-(trifluoromethyl)phenyl]tetrahydrofuran (see H.Ebel et al., PCT Int. Appl., 2010070032, Jun. 24, 2010) with2-aminoethanol.

32. Example 58 was isolated from the racemic mixture via supercriticalfluid chromatography (Column: Chiralcel OJ-H, 5 μm; Eluent: 4:1 carbondioxide/methanol containing 0.2% isopropylamine), and was the second ofthe enantiomers that eluted from the column. The first-eluting materialwas the enantiomer of Example 58, and exhibited an IC₅₀ of 1040 nM. Theabsolute stereochemistry of Example 58 was assigned on the basis of itslower IC₅₀ (see Table 1), in analogy to the other compounds describedherein.

33. 1-Chloro-2-fluoro-4-iodo-5-methoxybenzene was used as startingmaterial; see J. M. Blaney et al., PCT Int. Appl., 2008150914, Dec. 11,2008.

34. Sandmeyer reaction of 4-chloro-2-(trifluoromethoxy)aniline affordedthe requisite 5-chloro-2-iodophenyl trifluoromethyl ether.

35. The requisite{cis-5-[4-(pentafluoroethyl)phenyl]tetrahydrofuran-2-yl}methanol wasprepared via Suzuki reaction of (5-formylfuran-2-yl)boronic acid with1-bromo-4-(pentafluoroethyl)benzene, followed by hydrogenation overpalladium on carbon. 1-Bromo-4-(pentafluoroethyl)benzene was preparedaccording to the method of W. Lambert et al., PCT Int. Appl.,2011017513, Feb. 10, 2011.

36. The requisite{cis-5-[4-(1,1-difluoroethyl)phenyl]tetrahydrofuran-2-yl}methanol wasprepared via Suzuki reaction of 5-bromofuran-2-carbaldehyde with2-[4-(1,1-difluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,followed by hydrogenation in the presence of ruthenium(IV) oxidehydrate.

37. Example 62 was isolated from the racemic mixture via HPLC (Column:Phenomenex Lux Cellulose-3, 5 μm; Gradient: 50% to 100% ethanol inheptane), and was the second of the enantiomers that eluted from thecolumn. The first-eluting material was the enantiomer of Example 62, andexhibited an IC₅₀ of 723 nM. The absolute stereochemistry of Example 62was assigned on the basis of its lower IC₅₀ (see Table 1), in analogy tothe other compounds described herein.

38. 1-Bromo-4-chloro-2-(difluoromethoxy)benzene was prepared accordingto M. Ge et al., U.S. Pat. Appl. Publ., 20070265332, Nov. 15, 2007.

39. In this case, reaction was carried out withdi-μ-chlorodichlorobis(ethylene)diplatinum(II) and water, to yieldintermediate tert-butyl[(1S)-1-{(2S)-5-[4-chloro-2-(difluoromethoxy)phenyl]-5-hydroxytetrahydrofuran-2-yl}ethyl]carbamate.

40. The trans isomer of Example 64(2-{[(2S,5S)-5-(4-chloro-3,5-difluorophenyl)tetrahydrofuran-2-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione)was also isolated from the final step. This compound had an IC₅₀ of 184nM.

41.(2S)-1-{[tert-Butyl(dimethyl)silyl]oxy}-5-[2-(trifluoromethyl)phenyl]pent-4-yn-2-ol(prepared in analogous fashion to the alkyne described in footnote 26)was converted to{(2S,5R)-5-[2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanolusing boron trifluoride diethyl etherate and triethylsilane.

42. Example 66 was a minor diastereomer isolated during purification ofExample 17, and was presumed to have the stereochemistry shown.

43. The requisite aryl starting material was prepared from theappropriate fluorinated aniline via halogenation with anN-halosuccinimide, followed by Sandmeyer reaction.

TABLE 2 HPLC retention time (minutes); Ex. Method of Mass spectrum #Structure Preparation m/z (M + 1) 72

Example 7¹ 2.16 minutes²; 487.3 73

Example 7¹ 2.20 minutes²; 487.3

1. The appropriate homochiral 2-aminopropan-1-ol was used in place of2-aminoethanol.

2. HPLC conditions. Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm;Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phaseB: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95%B over 4.0 minutes, linear; Flow rate: 2 mL/minute.

Cell-Based γ-Secretase Assay with ELISA Readout

The ability of compounds to modulate production of amyloid beta proteinAβ(1-42) was determined using human WT-APP overexpressing CHO cells.Cells were plated at 22,000 cells/100 μL well in 96 well tissue culturetreated, clear plates (Falcon) in DMEM/F12 based medium and incubatedfor 24 hours at 37° C. Compounds for testing were diluted in 100% DMSOto achieve an eleven points, half log, dose response for IC₅₀determinations. Compounds were added in fresh medium to achieve 1% finalDMSO. Appropriate vehicle or inhibitor controls were added into controlwells individually to obtain minimum or maximum inhibition values,respectively, for the assay signal window before the plates wereincubated for ˜24 hours at 37° C. This procedure produces conditionedmedia in each well which is tested for Aβ(1-42) levels in the ELISAdetection step described next. The remaining cell cultures in each wellare also tested for cell toxicity as described below.

Coating of ELISA assay plates was initiated by addition of 50 μL/well ofan in-house Aβ(1-42) specific antibody at (3 μg/mL) in 0.1 M NaHCO₃ (pH9.0) into black 384-well Maxisorp® plates (Nunc) and incubated overnightat 4° C. The capture antibody was then aspirated from the ELISA assayplates and plates were washed via (2×100 μL to 4×100 μL) washes withWash Buffer (Dulbecco's PBS, 0.05% Tween 20). 90 μL/well of BlockingBuffer (Dulbecco's PBS, 1.0% BSA (Sigma A7030)) was then added toplates. Ambient temperature incubation was allowed to proceed for aminimum of two hours. Blocking buffer was then removed and 20 μL/wellAssay Buffer (Dulbecco's PBS, 1.0% BSA (Sigma A7030), 0.05% Tween 20)was then added. At this point, 40 μL (in duplicate) of experimentalconditioned media (described above) were transferred into wells of theblocked ELISA plates containing the capture antibody, followed byovernight incubation at 4° C. Cell toxicity was also measured in thecorresponding remaining cells after removal of the conditioned media forthe Aβ(1-42) assay by a colorimetric cell proliferation assay (CellTiter96®AQ_(ueous) One Solution Cell Proliferation Assay, Promega) accordingto the manufacturer's instructions.

After overnight incubation of the ELISA assay plates at 4° C., unboundAR peptides were removed via (2×100 μL to 4×100 μL) washes with WashBuffer. Europium (Eu) labeled (custom labeled, Perkin Elmer) Aβ(1-16)6e10 Monoclonal Antibody (Covance #SIG-39320) was added, (50 μL/wellEu-6e10 @ 1:10,000, 20 uM EDTA) in Assay Buffer. Incubation at ambienttemperature for a minimum of 2 hours was followed by (2×100 μL to 4×100μL) washes with Wash Buffer, before 30 μL/well of Delfia EnhancementSolution (Perkin Elmer) was added. Following a one hour ambienttemperature incubation, the plates were read on an EnVision plate reader(Perkin Elmer) using standard DELFIA TRF settings. Data analysisincluding inhibitory IC₅₀ determination was performed using nonlinearregression fit analysis (in-house software) and the appropriate platemean values for the maximum and minimum inhibition controls.

TABLE 3 Biological Data for Examples 1-73 Ex. # Aβ 42B IC₅₀ (nM)^(a)IUPAC Name 1  211^(b) 7-(4-methyl-1H-imidazol-1-yl)-2-{trans-2-[2-(trifluoromethyl)phenoxy]cyclobutyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2  300^(b)7-(4-methyl-1H-imidazol-1-yl)-2-{trans-2-[2-(trifluoromethyl)phenoxy]cyclopentyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 3    60.6^(b)2-{trans-2-[(6,7-difluoronaphthalen-1-yl)oxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 4 4832-({3-[4-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 5 1402-{cis-2-[4-fluoro-2-(trifluoromethyl)phenoxy]cyclopentyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 6  257-(4-methyl-1H-imidazol-1-yl)-2-({(2S,3S,5R)-3-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 7   73.52-({(2S,4R,5S)-4-Fluoro-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione8    14.3^(c) 7-(4-methyl-1H-imidazol-1-yl)-2-[(1S)-1-{(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 9     9.1^(c)2-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione10    3.34 2-[(1S)-1-{(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione11   40.5 7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 12 7257-(4-methyl-1H-imidazol-1-yl)-2-({(2R,5S)-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 13 2367-(4-methyl-1H-imidazol-1-yl)-2-({cis-2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, formate salt 14  1040^(b) 7-(4-methyl-1H-imidazol-1-yl)-2-({trans-2-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, formate salt 15   29.97-(4-methyl-1H-imidazol-1-yl)-2-({trans-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, formate salt 16   96.67-(4-methyl-1H-imidazol-1-yl)-2-({cis-6-[4-(trifluoromethyl)phenyl]tetrahydro-2H-pyran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, formate salt 17   38.47-(4-methyl-1H-imidazol-1-yl)-2-({(2S,4S,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 18  162-({(2S,5R)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione19 1460 2-[(4R)-3-(3,4-difluorophenyl)-4,5-dihydroisoxazol-4-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 20  1360^(b) 7-(4-methyl-1H-imidazol-1-yl)-2-{trans-3-[3-(trifluoromethyl)phenoxy]cyclopentyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 21 1887-(4-methyl-1H-imidazol-1-yl)-2-({2-[3-(trifluoromethyl)phenoxy]cyclopentyl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 22  789^(b)7-(4-methyl-1H-imidazol-1-yl)-2-{trans-3-[2-(trifluoromethyl)phenoxy]cyclobutyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 23  982-{[3-(4-chlorophenyl)cyclohexyl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 24 5632-[cis-2-(3,5-difluorophenyl)cyclopentyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 25 5612-[cis-2-(3,5-difluorobenzyl)cyclopentyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 26 3032-(trans-3-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}cyclobutyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 27 4697-(4-methyl-1H-imidazol-1-yl)-2-{cis-2-[2-(trifluoromethyl)phenoxy]cyclobutyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 28 5912-[2-(4-chlorophenoxy)cyclohexyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 29  802-{[(1R,3S)-3-(4-chlorophenyl)cyclohexyl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione30  711^(c) 2-({3-[2-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydroisoxazol-5-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 31 3532-({3-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 32 4292-({3-[2-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 33  217^(b)7-(4-methyl-1H-imidazol-1-yl)-2-{trans-2-[3-(trifluoromethyl)phenoxy]cyclobutyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 34 1202-{trans-2-[4-chloro-2-(trifluoromethyl)phenoxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 35 1622-{trans-2-[(7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 36  146^(b)2-[trans-2-(3-chloro-4-fluoro-2-methylphenoxy)cyclobutyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 37 1582-{trans-2-[4-chloro-3-(propan-2-yl)phenoxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 38 1647-(4-methyl-1H-imidazol-1-yl)-2-[trans-2-(naphthalen-1-yloxy)cyclobutyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 39 1122-{trans-2-[(7-fluoronaphthalen-1-yl)oxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione40 153 2-{trans-2-[3-fluoro-2-(propan-2-yl)phenoxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 41 1572-{trans-2-[2-chloro-3-(trifluoromethyl)phenoxy]cyclobutyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 42 1172-{[5-(3,4-dichlorophenyl)tetrahydrofuran-2-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 43    27.6^(c)7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 44   52.12-{[(2S,5R)-5-(4-chlorophenyl)tetrahydrofuran-2-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 45    26.6^(c)7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[4-(pentafluoro-lambda~6~-sulfanyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 46   60.37-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[4-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 47    15.7^(c)2-({(2S,5R)-5-[3-fluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione48   63.8 2-{[(2S,5R)-5-(4-cyclopropylphenyl)tetrahydrofuran-2-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 49   21.62-{[(2S,5R)-5-(4-chloro-2-methoxyphenyl)tetrahydrofuran-2-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 50  112-[(1S)-1-{(2S,5R)-5-[2,3-difluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione51 ^(‘)   8.35^(c) 2-[(1S)-1-{(2S,5R)-5-[3-fluoro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione52  15 2-[(1S)-1-{(2S,5R)-5-[2-methoxy-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione53   29.1 2-[(1S)-1-{(2S,5R)-5-[2-chloro-4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione54   11.4 2-{(1S)-1-[(2S,5R)-5-(4-chloro-2,5-difluorophenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 55    5.48^(c) 2-{(1S)-1-[(2S,5R)-5-(4-chloro-3,5-difluorophenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 56   81.27-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[3-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 57   11.12-{(1S)-1-[(2S,5R)-5-(4-chloro-5-fluoro-2-methoxyphenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 58   14.52-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione59 157 7-(4-methyl-1H-imidazol-1-yl)-2-({cis-5-[4-(pentafluoroethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, hydrochloride salt 60   73.32-({(2S,5R)-5-[4-(1,1-difluoroethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 61   24.62-[(1S)-1-{(2S,5R)-5-[4-chloro-2-(difluoromethoxy)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione62   13.3 2-{[(2S,5R)-5-(4-chloro-3,5-difluorophenyl)tetrahydrofuran-2-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 63   73.37-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 64  73.5 7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,4R,5R)-4-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 65  26.8 2-({(2S,5R)-5-[4-chloro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 66   33.52-[(1S)-1-{(2S,5R)-5-[4,5-difluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione67    5.78 2-{(1S)-1-[(2S,5R)-5-(3,4-dichloro-5-fluorophenyl)tetrahydrofuran-2-yl]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 68   24.22-[(1S)-1-{(2S,5R)-5-[4-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione69    7.84 2-[(1S)-1-{(2S,5R)-5-[4-chloro-5-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione70  10 2-[(1S)-1-{(2S,5R)-5-[4-chloro-3-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione71   52.4 7-(4-methyl-1H-imidazol-1-yl)-2-[(1S)-1-{(2S,5R)-5-[5-(trifluoromethyl)thiophen-2-yl]tetrahydrofuran-2-yl}ethyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 72   46.4(3S)-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 73   19.8(3R)-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-({(2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione ^(a)ReportedIC₅₀ values are the geometric mean of 2-4 determinations. ^(b)IC₅₀ valueis from a single determination. ^(c)Reported IC₅₀ value is the geometricmean of ≧5 determinations. ^(d)Not determined

We claim:
 1. The compound2-[(1S)-1-{(2S,5R)-5-[4-chloro-5-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.2. A pharmaceutical composition comprising the compound according toclaim 1 in admixture with at least one pharmaceutically acceptableexcipient.
 3. A method for reducing the production of amyloid betaproteins in a human in need thereof comprising administering atherapeutically effective amount of the compound according to claim 1 tosaid human.
 4. A method for treating Alzheimer's disease in a human inneed thereof comprising administering to said human a therapeuticallyeffective amount of the compound according to claim
 1. 5. Apharmaceutically acceptable salt of the compound2-[(1S)-1-{(2S,5R)-5-[4-chloro-5-fluoro-2-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.6. A pharmaceutical composition comprising the compound according toclaim 5 in admixture with at least one pharmaceutically acceptableexcipient.
 7. A method for reducing the production of amyloid betaproteins in a human in need thereof comprising administering atherapeutically effective amount of the compound according to claim 5 tosaid human.
 8. A method for treating Alzheimer's disease in a human inneed thereof comprising administering to said human a therapeuticallyeffective amount of the compound according to claim 5.